GOVERNMENT OF THE UNITED STATES OF AMERICA + + + + + FOOD AND DRUG ADMINISTRATION + + + + + PUBLIC HEARING + + + + + ELECTRONIC SUBMISSION OF REGULATORY INFORMATION

AND CREATING AN ELECTRONIC PLATFORM FOR ENHANCED INFORMATION MANAGEMENT + + + + + Monday December 18, 2006 + + + + + 9:00 a.m. PANELISTS PRESENT: JANET WOODCOCK RANDALL LUTTER RANDY LEVIN ARMANDO OLIVA KEVIN FAIN LANA SKIRBOLL KEN BUETOW BARBARA MITTLEMAN CLARK NARDINELLI Deputy Commissioner Panelist Panelist Panelist Panelist Panelist Panelist Panelist Panelist

The transcript constitutes the minutes from the public hearing held on
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December 18, 2006. A-G-E-N-D-A Presentations to the Panel S. Albert Edwards TAP Pharmaceutical Products...............10 Thomas W. Littlejohn Piedmont Medical Group....................34 Ron Celeste, ThinSpring...................55 Tom Klaff, Surety.........................97 Nancy Smerkanich Octagon Research Solutions...............113 Mark Scheineson, Alston & Bird, LLP......138 Debra Bremer, Pfizer.....................150 Diana McKenzie, Amgen....................157 Sue Dubman, Theravance...................161 Bob Beck, Fox Chase Cancer Center........167 Diane Paul, CRIX . . . . . . . . . . . 173

Dan Ruggles, Liaison Technologies . . . 178 Mark Adams, Booz Allen Hamilton . . . . 183 Ed Tripp, Abbott Laboratories . . . . . 211 Bill Rosen, Pfizer . . . . . . . . . . 225 . . . 253

John Rapoza, JRRapoza Associates Ari Kaliannan Newtech Global Solutions

. . . . . . . 255

Mark Rutkiewicz, AGA Medical. . . . . . 263

Presentations to the Panel (cont.) Jason Rock, Global Submit . . . . . . . 287 Laurie Rose, SAS . . . . . . . . . . . 307 . . . . 328 . . . 335

Harry Fisher, Northrop Grumman Robert Cothran, Northrop Grumman

Terence Zagar, Northrop Grumman . . . . 347 Public Comments Bob Bard, Aastrom Biosciences . . . . . 363 Michael Brennan, Centocor . . . . . . . 367 Bill Kubeck, Steeple Laboratories . . . 368 Antoinette Azevedo e-Submissions Solutions . . . . . . . . 372 Madeline Palla Animal Health Institute . . . . . . . . 375 Stephanie Vatleit Animal Drug Alliance . . . . . . . . . 376

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P-R-O-C-E-E-D-I-N-G-S 9:44 a.m. DR. WOODCOCK: Janet Woodcock. Good morning, I'm

I'm Deputy Commissioner for

Operations at the Food and Drug Administration and I'll be serving as the presiding officer at this hearing. On behalf

of the Commissioner of Food and Drugs, Andrew von Eschenbach, I'd like to welcome you to this public hearing on electronic submission of regulatory information and also on creating an electronic platform for enhanced information management. With me today on the panel that will be listening to the presentations are: Dr. Ken Buetow who is Associate Director for Bioinformatics and Information Technology at the National Cancer Institute; Mr. Kevin Fain who is Associate Chief Counsel, Food and Drug Administration; Dr. Randy Levin, Director for Health and Regulatory Data Standards at Food and Drug Administration; Dr. Randy Lutter, Associate Commissioner for Policy and

Planning at FDA; Dr. Armando Oliva, Deputy Director for Bioinformatics in the Office of Critical Path Programs at FDA; and Dr. Lana Skirboll, Director of Policy and Planning at NIH. And it's no accident that NIH and FDA We have a great

are together on this panel.

deal of both agencies' interest in these various topics. So first let me describe briefly the issues we're going to be talking about today and then I'll review the format for this hearing. FDA and NIH is interested in

hearing about issues concerning the feasibility and effect of an all-electronic submission environment as well as issues related to the electronic regulatory information exchange platform. Over the last

decade FDA has been moving toward transforming all regulatory submissions from paper to electronic means. For example,

we've issued regulations related to voluntary

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electronic submissions of regulatory information which many of you are familiar with. We've also issued numerous guidance

documents to assist in the submission of these various regulatory documents in electronic format. We've also collaborated

with manufacturers, with standard development organizations, with healthcare information suppliers and other government agencies to develop data standards and build databases for sharing certain clinical trial information. NIH has also in the last five

years been extremely interested in sharing clinical trial information on behalf of its investigators and the research it pursues. To help us answer our questions related to these two issues, we published in the Federal Register on November 21, 2006, an invitation to interested organizations and individuals to participate in making presentations at today's meeting specifically addressing the questions that were listed in the notice. These questions were divided

into the two topics.

The first set of

questions addressed the transition from paper submissions to electronic submissions, related costs, interested in time spent and how to implement this transition. Now we

recognize there are a broad range of FDAregulated products and that they're on a spectrum of experiencing electronic submissions right now. Some product areas

such as pharmaceuticals, there's a great deal of electronic submission. In other areas,

much less to no electronic submission and few associated standards. And therefore, we

recognize that whatever we do we're going to have to take a step-wise approach to implementation depending on the particular area on where we're starting and that will probably influence how long it would take to get there. Now the second set of questions relate to the concept and feasibility of an

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electronic platform that would facilitate the exchange of clinical research information and regulatory product information and the role of the public-private partnership in the creation of such a platform. Our experience

to date has shown that, although we may have the standards in certain areas for electronic submission, we don't perhaps quite have the network. Fourteen people signed up today to help answer those questions and we'll hear from those folks first. When that is done

and if time permits we'll open the floor to anyone else who may wish to address those questions. If you're a scheduled speaker, we

request you stay within the allotted time and I will make sure you do. Before we go on, let me stress this is a listening exercise for FDA and the NIH. We really want to hear what you have to We are having this

say on these issues.

meeting transcribed, we hope, and the members of this panel and their staff will pay

careful attention to what is said today as we decide our future course. And I expect that

you can look forward to prompt action from us on these matters. The direction will depend The

in part upon the input we receive today. docket will continue to stay open until February 16, 2007 to receive additional comments.

Now there are several housekeeping items I'd like to address. Number one,

please restrict yourselves to this room, the hallways, the stairs if you like and the lavatories, and do not move otherwise about the building because it's an FDA facility and there are other people working. have only an hour. At lunch we

There is across Fisher's

Lane a cafeteria-style public restaurant that you can go to and there are some other restaurants down. go to your left. You go out this door and So B but we have talked to

the folks across the way and told them they

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may expect a larger group today, so hopefully they will be ready and so we can all reconvene promptly at the time for the afternoon. So we have a very busy day and

I'd like to begin with our first speaker. Okay, our first speaker is Dr. S. Albert Edwards, who is the Director of Regulatory Affairs at TAP Pharmaceutical Products, Inc. Dr. Edwards. DR. EDWARDS: much. Okay, thank you very He will speak for 30 minutes.

I'm here today in my current role as

the Director of Regulatory Affairs and Operations. If I were speaking to you 20-

some years ago, and I'm not going to divulge the exact number of years, I could say I'm Al Edwards and I'm here talking to you from the FDA. So I've kind of sat on both sides of

things and I would say to you initially I wish in my lifetime early on I had access to electronic submissions to have done my job. The greatest enemy I guess that I faced at FDA in my time was the fact that I would get

to that very, very last volume in the NDA and then I'd have to go into the documents room and I'd have to try and find it. Documents

rooms then got closed and secured which was a good idea at FDA at the time, but then it put all the documents in the control of the document clerk and if you wanted your volume soon, you had to come up with an incentive plan. And my incentive plan was to always

turn in my volume request with a suitable incentive, okay? I'll talk more about more

formal incentives later, but those kind of things were needed. Back to present day. I want to

share with you eight observations that I have about electronic submissions. Those span

about the 10 years of experience that I've had and this next slide will show you what TAP's experience has been completing about 700 ECTD submissions to date. We did a

complete conversion in September of `05.

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That conversion included all original INDs, supplements and amendments. The conversion

also included all original INDs and amendments. And the last thing we did was So

convert all of our existing applications. we are a 100 percent ECTD shop. FDA is our customer. I can

reinforce that because I sat on the other side of the fence many years ago. I'm not

going to take time to read this entire slide, and Dr. Woodcock, when I get to my allotted time I know you're going to cut me off. everybody has my handout. Overall it has So

taken TAP some time to put the ECTD process in place. I want to emphasize that that's

process and technology on our side of the fence. well. I suspect it will be on FDA's as We have some improvements along the

way and that is we intend to control content and meta-data from authoring through submissions to archival. We believe that the

electronic tool sets are currently available for others to manage information and complete

ECTD submissions, as well. Let me take you on my travels through these general observations. of footnotes along the way. A couple

Number one, I

recently learned in an important meeting that adult audiences really won't listen to you unless you give them about five why's for everything you tell them. So you will see

"why" pop up on the screen here very often. That's to convince you or at least open your mind to my points. Some of my points will

be, `Oh yes, Al, we already know that. Please go on.' Some of them will be rather

controversial and so that's kind of the span of where we're going today. Number one. We, meaning FDA and

industry, should be a partnership, must work closely together and listen attentively to each other's concerns. Why? Computers are

fussy beasts and the information must not be changed when it's moved from one electronic

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environment to another.

Two, second why,

again my former life as a reviewer. Reviewers depend on this information. their day-to-day feeding and care that happens, to perform their job functions. Also, the industry depends on this information submitted to support and maintain healthcare product approvals. Why again? If It's

electronic systems cannot talk to each other successfully and share unchanged information, the process can be compromised. I'm not

saying it's compromised every time, I'm saying it can be. Observation number two. We must

carefully select and closely supervise any third party that may handle electronic systems and any information stored, either by FDA or by us in industry. This is contract

organizations that produce, transmit and otherwise interface, touch e-submission information. Why? The lifecycle of a

healthcare product, the development, marketing of a prescription drug for

instance, and I know there are other products at issue here, is a long-term process that could last decades. In contrast to that why,

the lifecycle of electronic systems and software is much shorter than a healthcare product lifecycle. Only third parties with

extensive appreciation for and commitment to managing the disconnect between this long lifecycle that we have for our healthcare products and the short cycle for systems and software should be considered suitable candidates for handling e-submission information. For the good of patients that

we serve we need to be in this for the long haul, folks. It's not just something you can Forget about it.

do on Sunday afternoon.

Again, still on observation two, why? Disconnects resulting in information

migration and retrofits are costly endeavors. Migration and data retrofits may be likely outcomes when inexperienced, low-bid, third

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party contractors are used.

Why?

This is

not only a dollar cost, it is a time cost. Migration and retrofits take time. are down. Systems

Delays disadvantage patients or

consumers, whether the delays originate in FDA or from us in the industry. Finally, confidentiality issues may arise due to incidental or inappropriate release of information. I would let you know

that most of these releases are not due to the system, they're actually due to humans. And so therefore staff at third party organizations have to be of suitable quality and they must be invested in the security of the information that we entrust to them. Very, very important. Observation number three. jointly learn how to handle and access repetitive e-submission information., Investigator Forms 1572s, and updates more efficiently and find ways to reduce that workload. Now I'm speaking about That's been my life for We must

prescription drugs.

the last, well, let's say 20-plus years. Let's not go there. time. But it's been a long

And we must find ways to more I would

efficiently handle that information.

say current industry submission systems are clogged with this information and it easily accounts for 20-50 percent of an average month's submission activities. The current trained labor force, and I think this was in the Federal Register as well, from e-submissions available within the U.S. is not sufficient today to handle the upward spiral of this workload if we add more to it. Why? I think we must change and

we must turn our attention to and use our limited resources to handle more difficult and challenging repetitive submission types. My example here is advertising and promotion submissions. This will require at a minimum

the integration of three-dimensional scanning and viewing. We all watch TV every day. We

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have camera phones. video.

There are other forms of

I think that you know - one of the

folks in my office always asks me, `What you're saying, can it pass the Washington Post test?' And I guess I would challenge

all of us, whether we have FDA jobs or NIH jobs, NCI jobs, industry jobs, if we said, we do this number of submissions electronically, but yet we almost have a whole group of submissions over here, advertising and promotion, other things, and we don't do anything for those. any way. We don't enable those in And I'll just

Would that fly?

leave that kind of as an open question. This brings me to a point I want to put in capital letters obviously and that is an e-submission paradigm should be an allinclusive one. Club Med. eSubmissions should be the We must

That's where we're going.

learn to use our systems, to use them repetitively for all submission types, if we are to maintain credibility with our external audiences. Commissioners' offices, Congress,

consumers we serve, corporate entities that we have to report into. Why again? Repetitive use of the

same tool set for multiple submission types will drive down the costs - cost is a key factor in this meeting - and provide some positive business cases and incentives for all to participate. Observation number four. We must

find a common ground to move forward with making e-submissions a requirement and not an option. We must provide incentives -

remember that Snickers bar, only now we're going to go for something bigger - to move from the current state of approximately 3-5 percent of all submissions sent to the FDA electronically to a 95 percent level very soon. 2009 is my example. Here I'm going to depart from the why's. I'm going to give you a few proposed Incentive number one, reduce the

incentives.

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PDUFA fee for those submissions requiring fees by some percentage or amount when a submission comes in in eCTD format. Incentive number two, reduce the PDUFA review clock by some number of days for applicable submissions in eCTD format. Proposed

incentive number three, grant a tax credit to those in industry, industry entities that have ongoing e-submissions programs. These

incentives are my opinions based on 10 years of working experience with e-submissions. They do not represent my prior experience at FDA, nor do they represent my current thinking of my employer, just so you know that. But I think we need to consider these

seriously and we need to be creative about what it is that will move us from - I think there are 200 people in this room. I think

the next time we meet we should have about 2,000 to hear this. We must also find ways to enhance and support FDA offices germane to esubmissions. FDA Office of Business Process

Support and the FDA staff that currently handle the electronic gateway. This has got

to be a requirement on the way to the 95 percent goal. there. There are great people out We at TAP

They do tremendous jobs.

would not be able to be where we are if it wasn't for these offices. And I want to

commend people that put these folks in place and the work they do every day. They have

clarified many things for us so that we can move ahead and convert to all-eCTD. Observation number five. Common

ground must include a master plan in which we can all invest. what? This plan should include

Things like what are we going to do

about E2B, SPL and the acronyms can go on, folks. I could spend another half hour on If I had

acronyms if I could remember, okay?

enough RAM up here to remember them all. When? We need to get serious

about the order of adoption of new standards

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for e-submissions.

The investment requires a

significant buy-in on the management chain on both FDA's side and within industry. (Sound system interruption) DR. EDWARDS: Stay tuned for We may be

further interstellar travel. leaving at any moment. Why?

Currently, electronic

systems deployed for the most part are highly customized, configured to meet individual needs and expectations. afford this diversity. We can't continue to Taxpayers can't

afford it, we in industry can't afford it, it's just too expensive. The electronic

silos that we've created by our current approaches will soon be obsolete due to evolving technology. There's no better time

to make a master plan than right now, today. There is no better time. Why? And you'll see, I sort of

got tired as I got to observation five because there are fewer and fewer why's. The

time interval grew much shorter so I couldn't

get all my why's in here.

Standards

development organizations are and will continue to produce more and different types of proposed standards for our consideration. We need to select those standards which will yield maximum benefit in an orderly manner. Again, a master plan is not something that can't change, it just needs to have an orderly process we can all invest in. Observation number six. The

master plan must include a schedule to control lifecycle development process. Before I put this next piece up, I am going to say that SPL is a very good thing that happened and I don't want what I've put up here to be in any way negatively interpreted about SPL itself. I'm only using that as an

example and as you can tell I now have some nice background music to lead into this controversial statement that I'm about to make. Thank you for that intro.

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Why?

One merely needs to look at

the impact of structured product labeling around October of 2005 for a justification for this. At least in our shop there were

two additional releases of software corrections and changes that were made in November and December. For those with

ongoing eCTD programs, this triggered multiple change requests and re-validations. This took some other people out of the work queue in our shop to deal with this. were unscheduled. Why? The inclusion of SPL was not Thus These

compliant with ICH eCTD requirements.

the eCTD software providers had to go outside the confines of ICH to produce a fix. So we

had to violate one standard in order to make another one work. I think we can do better.

The disconnect between the SPL and the ICH eCTD requirements to me would have become evident had there been adequate pilot testing and we could have considered some appropriate alternative measures to move that forward.

Observation number seven.

We must

include a Plan B, not to be confused with the other Plan B, okay? This is a computer

process now, not another process that also was Plan B, in our master plan. Why? We

must have an alternative in this master plan, a Plan B when the electricity goes out or a disaster strikes. a CD-ROM. I have with me in this bag

I also have my little thumb drive.

If the presentation wasn't present here, maybe I could go to Dr. Levin's computer, we could rig this up and I could give my presentation on a - you know, continue. Because I have backup. And so for any plan The best

we have, we've got to have backup.

example I can give here are prescription 15day safety reports that we need to keep turning in, whether the lights are on in my shop or whether they're on in Washington or not. I tell this story often, that during,

not an eCTD NDA, but an eNDA, about five or

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six years ago a little squirrel gave up his life and took us completely out of publishing because he decided to jump across this generator grid about two miles from our facility in Lake Forest, Illinois, and that took out the entire grid for about four hours. So you need to have a Plan B. We all

need to have one. Why? We must continue to perform

our jobs when electronic systems are not available. When an outage occurs, we need to Why? It's just good

go on, get things done.

business to have a disaster recovery plan for these critical electronic systems. Each

party, again, industry and FDA should know when the other party is down. We shouldn't

be trying to send electronic systems in if FDA's systems are down. If our systems are

down, we should be notifying FDA that they're down and why they're down and how long they'll be down. Observation number eight. And now

you can tell I really got tired because there

are no why's to this one, okay?

But we must

bring the correct focus and attention to the required infrastructure surrounding esubmissions. it's process. That's not only technology, but We must find a way to get the

same level of attention and appreciation for e-submissions as is currently accorded the content of a new drug application. Again, my

former life as a reviewer, I know how important NDAs are and there has to be a match now between meta-data and how it gets transmitted and the content. If you don't

get all the content because the meta-data is screwed up, it doesn't matter and that reviewer needs access to everything. So far, Dr. Woodcock, you have not cut me off. Okay. I'm going to quickly go We must quickly I

through the conclusions.

work - I'm sorry, we must work together. must work quickly. parties. Carefully select third

We must learn how to efficiently

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handle and access repetitive information. must find common ground to move forward in making e-submissions the requirement. The

We

common ground must include a master plan. That master plan must include a controlled lifecycle development process. The master

plan must include Plan B, and meta-data and infrastructure must equal the content of esubmissions in terms of importance. To whom much is entrusted, much is expected. I don't know who the author was, Or, we must all hang

but it's a great thing.

together lest we all be hung separately. Benjamin Franklin said that. As far as I'm

considered it's truly time to put away our perceived differences, move e-submissions from a 3-5 percent level of participation to the 95 percent level in the next two years. I want to thank FDA, thank you Dr. Woodcock for allowing me to speak. for your kind attention. DR. WOODCOCK: Thank you, and do Thank you audience

the panelists have any questions for Dr.

Edwards?

Randy. DR. LEVIN: Yes, I have two Is

questions.

One regards the incentives.

the candy incentive out of the question? (Laughter) DR. EDWARDS: No, we just need to

talk to Mars, the candy company. DR. LEVIN: My question is about

your comment about our labor force is not sufficient. sufficient? bit? DR. EDWARDS: I think that - and What kind of skills are not Can you expand on that a little

Randy, I'll just give you the experience in my shop. People need to be able to pay

direct attention to a computer screen for 8plus hours. to do. That's the first thing they need

They need to be extraordinarily

vigilant in terms of what they see on that screen to see if there are any errors or omissions so that we can produce a viable,

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quality product that you or your reviewers want to look at. necessarily PhD's. school graduates. Those people are not Some of them are high For every, let's say, four

people that I bring into my shop, usually two of them survive because it is a unique skill set of someone who will pay that much attention to a computer continuously. admit I can't do it personally. I'll

I can't

spend eight hours of my day staring at a computer screen, but that's what it takes to put an eCTD together. And so we just need to

be conscious of the fact that as we move forward, we don't have good parameters to pre-test people to understand who can do a good job and who can't. DR. WOODCOCK: DR. BUETOW: Ken? Implicit in your

presentation, which I should thank you is very useful, is the need for this infrastructure to be comprehensive, but also the need to actually have a master plan for its deployment, if that's a fair

interpretation.

But I was curious.

Can you

give us any insight - this is obviously huge - where would be the sweet spots to hit some of these repetitive tasks that you've mentioned? activity? DR. EDWARDS: High-priority What would be high-priority

activities, I can't remember which slide it is, but I think we have to go to advertising and promotion submissions. I know that's

very controversial, I know there's a lot of resistance there. Before I came to the FDA I

worked at MD Anderson Hospital in Houston on the wards. The way the hospital

administrator let me on the wards to do drug monitoring as a pharmacist because of course they believe a pharmacist couldn't do it. said I'll give you the most difficult ward first. You prove to me you can do it there, He

you can go anywhere in the hospital after that. So I guess, and it reflects a little

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bit of my personal opinion.

I think we need

to do the difficult stuff first to prove to people that we can move on. DR. WOODCOCK: from the panel? Armando. How long did it take Any other questions

DR. OLIVA:

your company to move to the all-eCTD environment once you made that decision? DR. EDWARDS: We carefully

monitored the eCTD both from the point of view of guidance documents and available software providers from July of 2000 through July 2003. We made a commitment at that time We produced our first test

on paper to move.

disk for Ken Edmunds and all these other wonderful people that work in business process support. May of `04 we produced our And my

first NDA in eCTD format in `04.

boss, who's also a very big supporter of this, came into my office and said so you've done the NDA. everything. 2005. So now show me you can do So that's what we had to do in I

So that's kind of our timeline.

think there are probably other experiences in this room that I'd refer you to. DR. WOODCOCK: Other questions? Our next

Thank you very much, Dr. Edwards.

speakers are Dr. Thomas W. Littlejohn, Medical Director of the Piedmont Medical Group and Mr. Doug Pierce, President of PeerMed, Inc. DR. LITTLEJOHN: Woodcock. Good morning. Thank you, Dr.

Thank you for

allowing my colleague and I the time to address this panel. Littlejohn. My name is Tom

I am the Medical Director of

Piedmont Medical Group which is an organization of independent clinical research sites in the two Carolinas and Tennessee. have been involved in clinical research for 20 years and have functioned as a principal investigator on over 300 trials. My I

colleague is Doug Pierce, President of PeerMed, Inc., a healthcare-formed company

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located in Virginia and North Carolina. We are here to address the issue of electronic data capture, storage and transfer as it applies to clinical research sites. We applaud the efforts of those who

are working to convert the traditional paper model into an electronic model. This

transition is picking up momentum and has been clearly shown to reduce costs, improve quality and accelerate the process. All of

the activity to date, however, assumes that with the exception of large academic centers with EMR, that the original data, the wellspring, if you will, at clinical research sites will be captured on paper and then transferred to a case report form, whether it be paper or electronic. These source

documents are sacred to the integrity of the trial and must be accurate, accessible and protected for many years. They must remain

under the control of the principal investigator and free from manipulation or tampering of any kind. They cannot be

reproduced.

For this reason they must remain

at the investigative site and review of them requires that the reviewer travel to the site to verify the data and its integrity. We are proposing a technology whereby the initial data can be captured electronically in the same manner as it is currently on paper and that the data can be validated, verified and protected more effectively. Additionally, this digital

source data could be reviewed by monitors, regulators or any other authorized party from a remote location. Adoption of this

technology would close the final gap that otherwise would continue to exist between a completely electronic environment and a paper one. I'll turn it over to Doug. MR. PIERCE: presentation. I'm in Dr. Edwards'

Which I'm going to do it

again, just in case you didn't get it. (Laughter)

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MR. PIERCE: second.

Bear with me here one

While I find this, I'm going to let

you know that I did not attend the why meeting and I have no why's. you all see? Thank you. Can

I can't see, I'm at the podium. However, I was

I didn't hit the why meeting.

at a meeting that said that when you start these kind of addresses, you should blaspheme famous authors. So for those of you who have

read Shakespeare's Julius Caesar, I'm sorry. We have gathered here not to praise paper, but to bury paper. (Sound system interference) (Laughter) MR. PIERCE: But this isn't the

first time we've gathered together to bury paper and paper is proving to be puzzling. want to talk about the puzzling persistence of paper. And I think the photograph below And it says, it shows We sit at a I

the title says a lot.

what we do maybe every day. desk. DR. LITTLEJOHN:

We've got a

keyboard, a mouse and we shove them aside to grab a legal pad and a pen. And you notice We have And

that the person is starting a list.

three very different ways to input data. it seems to me that we have to examine the power of paper and the paper interface and

understand it if we're going to in fact bury it. So we'll be talking about the puzzling

persistence of paper today. Benefits of electronic data capture we all know very well, especially in this room. We have rapid access to data. We have fewer We

have higher quality of data.

queries and faster resolution of the queries that we do get. We have better tracking of

adverse events, less time to data log and of course substantial cost savings. And

obviously those are the reasons why EDC is gaining momentum in the market and that's a wonderful thing. However, there are barriers to

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adoption.

The rate of adoption is not as It's not as fast as There are technological For

fast as we would like. many people thought.

constraints that are holding us back.

example, if it's a web-based EDC we have internet access or do we not have internet access. up? Do we have broadband? Is it dial-

Is it every other day?

You know, that

sort of things.

We have connectivity issues There are hardware All

within a research site.

and software deployment issues involved. those things limit and slow the growth of EDC.

There's also personnel constraints and I almost said behavioral constraints because I think that's probably a better word. We have attitudes toward work and work

flow and what traditional responsibilities have been and which will change when EDC systems are brought onboard. certain level of technological sophistication, of savvy, of comfort that EDC systems seem to demand. But the interesting There's a

question to us is even when the technological constraints and the personnel constraints have been met, in the very best setting why is it the paper source docs are still being used? Why is it that even with some of the

best EDC systems you can get the coordinator initially captures the data on paper? Well,

to understand that we have to understand the power of pen and paper. If it was a computer

system, paper and pen, we would say the modern paper and pen interface is the result of 5,000 years open source global collaboration. It's the most well developed,

shared, open source way to gather data ever. The early data wasn't good. You've seen it

on the cave walls, but we quickly moved from the rock and the chisels to paper and we've been developing it forever. And almost every

human being on the planet knows what to do when you hand them paper and a pen or pencil. So it's been around a long time and it's part

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of us.

It's the original It's flexible. If

graphical user interface.

you forget something on your list, you can add it. I could have added "wise" to my It's familiar. When

thing here, but I can't now. It's friendly.

No one's intimidated.

you hand a legal pad to somebody, they don't go oh, I don't do legal pads. You don't have somebody looking around trying to find their legal pad like I was doing. So it's very friendly, familiar Now, let's

and it works very, very well.

take some of these ideas and look at paper source documents. Paper source documents

allow for structured and free-form entry of data. In other words, the paper source docs

that you've made following the protocol have blanks and check boxes for structured data, data that you know the protocol asks for. But the beauty of paper is if you need to add something on the fly, you just write a marginal note. You circle. You sign. You

can add data on the fly.

They're simple.

They require minimal training.

Data capture

on paper source docs is a very unintrusive thing. a room. Coordinator and patient are there in The coordinator is taking data down.

No one has to turn around and type in data. There's no machines to wheel in, et cetera. And the most important reason we think paper source documents have been so hard to kill is that there's just a lot of very important data, important for the case history, important for the trial that is not a data point to be entered into the data management. It's not even and it shouldn't be on the electronic case report form, but you've got to have it. And when we've talked to

coordinators and monitors, they insist on seeing it. So there is lots of data, what we

call data, and by "data" it may be marginal notes that have to be captured, but that aren't passed on downstream that force people to use paper source docs which keeps us sort

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of you know tied to paper. So what can be done about that? Nothing. No, here we go. We think one

solution is to recreate paper source documents keeping the 5,000-year-old interface, the 5,000-year-old data entry methods that we know and love, but change the paper. It's not the interface, it's not the

way we enter data that's the problem, it's paper. So what we propose doing is replacing

paper with a tablet PC which of course you are very familiar with. Recreating the

source documents that look and feel just like paper source documents that contain structured data, check boxes, pulldown lists, et cetera, but that also allow you to write marginal notes, to ink comments about blood pressures, et cetera. The data itself is

then - the data points extracted from the forms and sent through a secure web portal straight into the ECRF that the sponsor is using. In addition to the data being

passed through, images of the form itself in PDF version are also captured and sent to the secure web portal. forms. These are the actual

These are the actual forms with the

checks and the marginal notes, the forms that have been assigned, and they reside there on the website where they can be reviewed from anywhere in the world by the sponsor's monitor, by regulators from the FDA, anyone who has authorized access can look at the source documents, the actual ones. If they

have any questions about data downstream they can go back up to the source, the wellspring of the data and look at what was done. addition, if it's an adapted trial, for example, and the source documentation needs to be changed, it can be changed in one place and pushed down to the local devices deployed in the field. When the study is over, research sites have the problem of keeping up with In

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their paper source docs.

There are, as you

well know, warehouses scattered around filled with paper source docs that supposedly are kept in a, you know, secure way. storm does those in. One good

So since the source

documentation are digital they can be moved to a long-term storage where again the forms and the audit trail can be reviewed at any later date. The benefits of this sort of

digital source documents are data is entered only once. Now, most of the time, even when

EDC is in place it's actually entered twice. It's written on paper first and then it's translated into the ECRF. Point of entry protocol-specific data validation. data is validated. Before the patient leaves, If there's a problem, you Simple,

can correct it there on the spot. intuitive, familiar interface. data capture.

Unobtrusive

As you all know, tablets are You can work on the fly. You can take a vital.

very unobtrusive.

You can set them down. You can pick it up.

Nothing gets in the way

of the coordinator-patient interaction.

A

secure audit trail is of course provided and that audit trail can be viewed from anywhere. And you can see exactly what was changed, when it was changed, who changed it and why. We believe a system like this would produce significant barriers to fraudulent data entry. All the research

sites nationwide globally would all be looking at the exact same source docs and you can trace not just the data that's passed downstream but what they actually did and who did it. Who signed what. You can see where It works in a

they signed it.

It's mobile.

disconnected state.

That means if you're not

connected to the internet, you're walking around your office, you take your data. When

you get back to your internet connection you sync up and the data is automatically loaded up to the website. If data standards are adopted

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freely, it plugs into any ED system.

This

system is only concerned about capturing initial data and then passing it on. would allow monitors, data managers, regulators to verify source documents from wherever they are. The savings to the It would solve the This

sponsor would be huge.

sort of dilemma of things like fixed unit pricing versus 100 percent source data verification. How can we verify enough data So

and yet save money and meet the budget? we think that a system such as this that

focuses on just the initial capture of data and that does it in a way that mirrors this old, old paper interface that we're used to using, but does it in a way that's modern and that allows us to verify data and securely transmit data would go a long way toward finally burying paper. Now, the FDA's role. Clearly, a

system such as this and any EDC system requires clear, consistent guidelines for data validation. We all have to be

validating data in the same way. the eSDI initiative are crucial. have compliance market-wide.

Things like We have to

Right now as

you all know of course there's islands of EDC systems. other. Some can communicate with each Some can communicate with EHRs and There's got to be from

EMRs, others can't.

the top down a consistent set of data transmission standards and we all have to use them. We believe that a system such as this supported by well established shared data transmission standards would go a long way toward helping investigators at the site level. It would make it easier for a new It

investigator to enter this line of work. would be clearer.

What was called upon for It would also

him or her would be clearer.

make post-market surveillance easier, safer and more affordable. So for all those

reasons we would like to see us move in that

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direction and really address the power of paper and then bury it. Questions? DR. WOODCOCK: Thank you. Are I have time left.

there questions from the panel? DR. OLIVA: specific?

Armando.

Can you be more

Exactly what exchange standards

are missing or are needed in this area? DR. LITTLEJOHN: Well, I think the

standards that the CDISC group is working on now where data is gathered in the same format and then can be transmitted into whatever back end system is being used, XML standards. You know, it doesn't really matter on what the standard is as long as we're using the same one and it's an appropriate data format to transmit via the net and share. So I

think the work's being done now, I just think we need to keep pushing it. We need to make

sure - and at some point there's got to be teeth. I mean someone has to say this is This is the standard that Otherwise I think we're

what we are doing. we are going to use.

going to go a long time in having partially compatible data standards in data transmission standards. DR. WOODCOCK: DR. BUETOW: Ken? Yes. The

longstanding debate of whether one should have structured data at point-of-collection or later in translation after collecting unstructured data. Do you want to come down

on that, on what side of the argument you come down on on that? DR. LITTLEJOHN: Well, both. I

hate to straddle the fence here.

I think the

beauty of digital source docs is that you can in fact have both. You should have both.

There's a lot of data that the protocol calls for that is structured data. Data has to be At

captured and captured in a certain way.

the same time there's got to be room to enter free-form data. I was talking to a monitor

last week and a very simple but clear

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example. pressure.

She was talking about blood And we take a patient's blood Well, Maybe

pressure, it's really, really high. what you always do is you just wait.

they just ran in, maybe they're late, maybe they're anxious, six cups of coffee. just wait and you take it again. You

Well, if

there's not room to write a note, literally a note saying, you know, I gave her five more minutes, she seemed anxious or nervous. took it again and this is what I got. I Then

you're left, what you do is you grab paper. I mean, you aren't going to not record that. Open up a chart, there's sticky notes everywhere. And as long as we have paper and

sticky notes we're still chained to paper source docs and this trail. has to have both. So I think it

I think the only solution

is we have a system that can accommodate both. DR. WOODCOCK: DR. LUTTER: Randy. Can you elaborate a

little bit more on what you mean by

validation guidelines? DR. LITTLEJOHN: MR. PIERCE: Absolutely.

Can I address that?

What needs to happen for something like this to be adopted by industry. For this to be

adopted by industry they need to know that the device, the technology, the software that we're developing is CFR 21 Part 11 compliant and that the FDA feels confident that these devices if constructed in the proper way would be acceptable, would pass an audit, for example. Some sort of collaboration,

cooperation from the agency to look at these type devices as they're being developed to reassure the potential customers which would be any particular sponsor would want to adopt the technology. So we would make a plea that

this sort of sharing of information and you know working together would help move this along greatly. DR. WOODCOCK: Is there an issue

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with the current definition of "source documentation" that exists within the FDA? MR. PIERCE: I don't think there's

- a source documentation is pretty clear. It's the initial capture of any information, whether it's an EKG, a blood pressure, you know and wherever it exists is the original source. So I don't think there's a problem.

Something that happens with electronic medical records, for example, because it doesn't lend itself easily to a clinical trial protocol, it's not uncommon for data to be written down on a piece of paper and then entered into the electronic health record. Well, what was on the paper is the actual source document according to your definition. So I think we eliminate that problem with this interface. DR. WOODCOCK: So what you're

saying is that the Part 11 issue is there needs to be clarification there, but conceptually there's not a problem with the definition of source documentation, it's more

the compliance, Part 11 compliance. MR. PIERCE: Right. We would just

like to see the guidelines to be a little more clear, concise, unambiguous and that there not be significant cost constraints to adopting them. DR. WOODCOCK: from the panel? Ken. While we're on Part Other questions

DR. BUETOW: 11. MR. PIERCE: DR. BUETOW:

Yes. So, would you

actually argue partially in answer to the question right before Dr. Woodcock's, you're arguing that we need additional specification a la Part 11 for the specific systems, for their definitions and validation over and above what's already in Part 11? MR. PIERCE: Well, I would submit

that the guidelines in their present form are rather vague and rather ambiguous and don't

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give I think industry comfort that spending a lot of money developing a system like this without knowing ahead of time that it would be acceptable is a problem. So there aren't

- it's not that the guidelines are wrong, we just, we need more clear and concise guidelines I think. More in depth. Any other questions

DR. WOODCOCK: from the panel?

Thank you very much. Thank you. Our next speaker

MR. PIERCE: DR. WOODCOCK:

will be Mr. Ron Celeste from ThinSpring. MR. CELESTE: thank you very much. Good morning and

I'd like to thank the

FDA very much for the opportunity to present this morning. I am going to, having only

really 15 minutes and five minutes for questions, I'm going to go through these slides some of them very rapidly. What I'd

like to do is start with a historical perspective of these submissions and get into what the current industry standards landscape looks like, then talk primarily at ThinSpring

servicing over 60 medical products manufacturers. Primarily going to address

the issues that our clients see in adopting electronic submission technologies across the board. Talk about submission lifecycle

management, the concept of a third party facilitation for these submissions and then again highlight some specific challenges we see in industry. You all remember computer-aided new drug application guidelines in the `80s. When I was at Baxter Healthcare the technology we had at that point in time really was not very conducive, was not conducive at all to real-time discussions between the reviewer and the applicant or sponsor manufacturer. They did enable

asynchronous communications where files could be sent back and forth and questions be answered and then files updated and sent back using graphics programs like Harvard

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Graphics, the old blue screen WordPerfect word processor and databases on the desktop, 286 processing power desktops. think we'd need anything more. tools were not integrated. We didn't get integrated desktops until the `90s with things like Microsoft Office. The portable document format, file We didn't DB3+. Those

format from Adobe didn't come out until 1994. Then Al Gore invented the internet and everything changed. We really view My second key

extensible markup language.

point is that extensible markup language as a file format is the key technology that can enable efficient and effective electronic submissions in any e-submission data platform. We've seen an explosion - this is my alphabet soup slide - an explosion of initiatives since the internet came to be with the browsers and the desktop capabilities that are available through a browser. I don't have time to go through all

of these acronyms.

It's full of TLAs and

FLAs, 3-letter acronyms and 4-letter acronyms. It would take me all 15 minutes to

get through all these, but key point at the end of this. RPS. Moving into the future you see

RPS stands for regulatory product

submissions and RPS is under the auspices of - in a standard controlled by HL7. We

believe that in all XML ECTD will be an efficient file format to deliver effective electronic submissions throughout industry. Key challenge for industry. purple 3-letter acronyms and 4-letter acronyms on the screen are existing enterprise systems that commercial manufacturers have in-house today. Enterprise resource planning systems, electronic document management systems, enterprise content management systems. key is that their electronic submissions tools and the tools that they use to The These

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communicate with the FDA need to integrate tightly with existing legacy information systems and solutions that are in-house already at these manufacturers. There is a roadmap that we've been following. We've talked about guidelines

that have been published and mandates that have come out of the FDA starting with the electronic labeling rule in 2004. This is a

timeline that we're following at ThinSpring in supporting our clients moving forward. do see ECTDs eventually being mandated, a potential proposed rule coming out of this meeting, becoming a final rule sometime possibly in 2007, late 2007. We also see We

RPS, the regulatory product submission, regulated product submission standard being adopted industry-wide. One of the challenges

we'll get to later though is harmonization of standards between the U.S., between the E.U., between Canada. XML is a data file format

that we believe is going to enable effective e-submissions. However, there does need to

be an agreement on standards and there does need to be more harmonization than we've seen today between ICH, HL7, CDISC and a variety of other standards bodies out there. Key challenge for the manufacturers, the sponsor applicants is that not all of them, especially the smaller and mid-sized manufacturing organizations have today the ability to manage XML data-centric and document-centric information. So an XML

infrastructure in-house that integrates with their existing enterprise solutions is a challenge that a number of the manufacturers are facing today. XML is a great technology

for improving data portability and data archiving. Dr. Edwards mentioned we need a

technology that has a long enough lifecycle to at least match the lifecycle of a medical product. XML technology and its ability for

archiving, I can open 20 years from now an XML file with a simple text editor. We have

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one client who is literally storing a deck vax with a clinical data management system from 30 years ago in Iron Mountain so that they can get access to that data when they need it. With an XML file, you can open that

file 20 years from now with a simple text editor. So from an archiving standpoint,

again, we firmly believe XML is the extensible markup language is the technology, the file format technology that enables an all-electronic e-submission platform. Hear a lot about what extensible markup language is. I wanted to talk a XML is not

little bit about what XML is not.

a single software package that you can buy and install and start using like Microsoft Word. It's a structured content markup

language that facilitates data exchange. It's not a single electronic submission standard. There are multiple standards.

There are XML standards for clinical data that are managed through CDISC. HL7 has the

RCRIM structure for defining medical product

data.

ICH has a number of standards.

The

electronic common technical document today, the backbone for the ECTD is XML, defined in extensible markup language. A key point for

the manufacturers and the people who are hands-on as Dr. Edwards mentioned, looking at that screen for eight hours a day is XML is not a single file. XML is not a Microsoft

Word document, it is not a .pdf file, and today again most manufacturing organizations have document management systems that are geared towards managing the lifecycle of a single flat file. XML needs to - you need to

have configuration management version status accounting tools that enable you to manage the structure, the content and the style or formatting of your submissions. Another key

point is XML content does not replace printed literature and that is an interesting scenario when you start talking about advertising and marketing materials and how

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content that is approved in extensible markup language file formats translates into printed material through different formatting and style sheets. This is a little difficult to see, but this is making the point again that XML is not a single file format. This is an

example of a structured product label file folder which contains content files, structural files and presentation or style sheet files. So again the industry challenge

is for the manufacturers is that we need to have tools that allow us the configuration management control for structure versus content versus style. We can have that same

structure - I'm sorry, the same content that gets approved again using the SPL example, the boxed warning structured product content gets approved by the FDA and posted on the National Library of Medicine. We can have

multiple formats or style sheets for presenting that approved content back at the sponsor manufacturer's location. They may

have a PDF style sheet to publish that information on their website. They send it

to perhaps an encapsulated postscript file to print that boxed warning on a physical container label when they do a product run on the shop floor. So the key is we need to be

able to maintain configuration management status accounting version control of the content, the structure and the presentation of our XML-based submissions. Full lifecycle management. Dr.

Edwards also mentioned that in their internal system at TAP they're looking towards improving the management of the meta data. Meta data is data about data. The meta data

and the content contained in their submissions throughout the entire product lifecycle. Again using the structured

product labeling example, most manufacturers are through the path of - the challenge of getting existing Word documents, existing PDF

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converted into XML and now are looking towards full lifecycle control. What do we

do after the submission is approved? The third party electronic submission facilitation, an important slide here. This is just another version of a

slide I presented back in 2004 at the Structured Product Labeling Challenge that the FDA published. The technology exists

today now much different from the early `80s and the mid-`80s to allow both real-time and/or asynchronous communication between the sponsor applicant and the FDA. Web-based

technologies and XML data file formats are those enabling technologies. Industry adoption challenges. A

key is minimizing system design complexity. We've heard earlier and we've had a bit of conversation about validation and having to re-validate every time there's a change in the tool set. Minimizing system design

complexity minimizes the validation challenge. And I have a final slide to

discuss that in more detail.

Component-based

content creation training and education. Again, remember XML is segregating structure from content from format. That is a

different paradigm for the users at the sponsors, the authors of these submissions at the manufacturing sponsor organizations to get used to. So there is a good deal of

education and training required. Intellectual property protection is a big concern of the manufacturers, especially when we're dealing with a new drug application and proprietary drug technology. Technology such as SAFE, Signatures and Authentication for Everyone. It's a

consortium that was formed to address electronic signatures and authentication within industry can be applied to help address this concern. Regulatory agency

standards harmonization I mentioned earlier. Very important that we see a higher level of

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harmonization between ICH, HL7 and CDISC. And then communication, communication, communication. today. That's what we're doing here

I think this is an outstanding forum

and I think we need to be doing more of this. My final point on system complexity. Here's an equation we've been

using for a number of years but you do need to see that complexity and the validation challenge of any system design increases significantly and exponentially as the total number of software packages and technologies used to create the solution are employed. And that's all I had. minutes for questions. DR. WOODCOCK: much. Anyone? Thank you very We have about two

Are there questions from the panel? All right. MR. CELESTE: Thank you for your

time. DR. WOODCOCK: break. We will now take a

We will take a break until 10:35 by

that clock right there and also by my watch.

So you have a few minutes, but we will resume promptly at 10:35. Thank you.

(Whereupon, the foregoing matter went off the record at 10:17 a.m. and went back on the record at 10:35 a.m.) DR. WOODCOCK: Joining us this

morning on the panel sitting in for Dr. Skirboll will be Dr. Barbara Mittleman also from NIH. Our next speakers are Dr. David

Hardison who's Vice President of Life Sciences at SAIC and Wayne Kubick who is Senior Vice President, Lincoln Technologies. Ready to go. DR. HARDISON: Good morning. I'd

like to thank Dr. Woodcock and the panel for this opportunity to speak today. Wayne

Kubick will be joining me for the Q&A after I give my remarks. Clinical Data Interchange Standards Consortium, better known as CDISC, wishes to commend FDA for the regulations

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guidance documents and specifications and their overall support for standards as part of the efforts to move towards electronic regulatory submissions. CDISC heartily

endorses the FDA proposal to move to an allelectronic submission environment for regulatory information and the creation of an electronic platform for enhanced information management across departments and divisions of the agency. CDISC is a global, open, multidisciplinary non-profit organization that has developed standards to support the acquisition, exchange, submission and archive of clinical trial data and meta data. CDISC

is the leader in the development of data standards for clinical research. CDISC

participants and stakeholders include more than 175 organizations representing academia, pharmaceutical companies, technology and service providers, institutional review boards and others interested in streamlining biopharmaceutical product development and

improving clinical data quality in healthcare. CDISC also has joint memberships

with HL7, PIMS, EMEA and CPATH Institute. Please check out CDISC.org for additional information. The mission of CDISC is to develop and support global platform independent data standards that enable information system interoperability to improve medical research and related areas of healthcare. The CDISC

standards are in different stages of their lifecycle. Several of the standards are

written as specifications in FDA guidance and we continue to work towards finalizing and improving these standards with your help. CDISC depends heavily on its volunteers. Data flow using CDISC standards including its link with healthcare. After

the presentation of Dr. Littlejohn and Mr. Pierce today we'll have to modify this to make sure we better illustrate capture at the

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point of care in our diagram which is where everything begins from the data standards world. CDISC supports the belief that

submissions in a standard electronic format will facilitate regulatory review processes at FDA and enable the use of common review tools that improve reviews. I underscore we

support the belief that these standards will improve regulatory review. Because of the

lack of a robust infrastructure in which our sponsor companies can support their electronic submissions, especially with respect to the CDISC standards. It makes it

very difficult to have a test bid - I knew the gremlins were going to come in at some point in time. It makes it very difficult to

test and ensure that an implementation of the standards can actually be received at FDA. So therefore having an infrastructure in place will accelerate and improve the standards that we are working on so hard right now. In addition, standards for

electronic submissions enable data

aggregation and the population of cross-study and cross-product databases that will vastly enhance the FDA's ability to perform safety assessments, identify trends and conduct product evaluations. Such knowledge

repositories would not be feasible without the submission of logically and semantically consistent data and information by manufacturers in a standard electronic format. The value of standards accrues to manufacturers as well. When applied from the

startup stage of a clinical study or program, standards have been shown to improve data quality and substantially reduce cost and time in the product development process for sponsors and other stakeholders in the industry. later. We will speak to these specifics

Most importantly, CDISC believes the

transition from paper to standard electronic submissions will lead to safer and more

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effective drug products to improve public health. One of the impediments to transitioning to an electronic submission environment is the requirement that this data or information must be in a standard format. Fortunately industry has been actively involved with the agency over the past decade to help develop and implement industry standards for the purpose of supporting electronic submissions. CDISC is the leader

in the development of data standards related to clinical research. Our members have

contributed collaboratively to the consensusbased CDISC standards development process. Most stakeholders in the industry are either in the process of implementing or making plans to implement these standards. Broad-

based technical knowledge and experience in the application of these standards are needed among all stakeholders, including industry and FDA personnel. CDISC is proud of the

fact that we're working with FDA to provide

adequate training in these standards in the coming year. Fortunately, both XML and

expertise and knowledge of the CDISC standards are increasingly prominent within the workforce. Education and training

courses are readily available at a reasonable cost. While the implementation of standards-based electronic submissions requires an investment of time and money, it also reduces operating costs and time-tomarket once the standards are in place. CDISC recently participated and partnered with the Gartner Group with support from PhRMA to develop a business case analysis that estimates the costs and benefits of standards implementation. While these costs

are very difficult to estimate particularly because of the absence of baseline information, the business case metrics indicate that there are substantial

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reductions in cost and time related to capturing, cleaning, analyzing and reporting clinical trial data, especially when standards are used at the startup stage of a clinical trial or program. Similarly,

regulatory reviewers will be able to spend less time on data manipulation and more time on the science when data are submitted in a standard format. Communication will also

improve between the agency and manufacturers such as reducing time for follow-up queries once a submission occurs. Over 50 percent of clinical trials involve a contract research organization, CRO, and an increasing number of trials involve electronic data capture vendors. Communications and data exchange among sponsors, CROs, EDC vendors and even project team members become much more cost-effective and easier when standards and electronic processes are employed. This is especially

true as we've seen in earlier presentations if we can harmonize standards across clinical

research and with healthcare so that data are entered only once at the site. This will

help relieve a lot of the burden of clinical investigators and create more incentives for their participation in clinical research. Therefore, CDISC heartily supports the 2-year industry transition time that is stated in the proposed rule for electronic regulatory submissions. Making the transition from paper to electronic submissions is hard work. CDISC would like to offer several recommendations to ease the transition. must take the strong position to drive manufacturers to make all electronic submissions in XML containing data in specified standard formats. The majority of FDA

industry organizations is prepared or is in the process of preparing to utilize CDISC standards for submission of clinical data for regulated biopharmaceutical products. This

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includes the CDISC study data tabulation model, the operational data model and define.xml. SDTM can be submitted to FDA in

the ECTD or the HL7 regulated product submission format. We would like to see the FDA adopt the ODM for electronic CRF data submissions in addition to using it as a transport format for define.xml meta data and SDTM and analysis data. This transport standard is

already familiar to most industry stakeholders. It can also facilitate auditor

reviews of electronic data capture environments at investigative sites. CDISC is driven by a mission that supports electronic submissions and data exchange that will enable translational research. To that end CDISC is working with

industry and FDA on standards to support electronic submissions for devices, genomics data and animal data. CDISC has already

published the SEND standard, the Standards Exchange of Nonclinical Data. Both SEND and

STTM are cited in study data specifications for the final ECTD guidance. Many of you - translational research is more rapidly bringing innovations from bench to bedside. For over five years

CDISC has formal relationship with HL7 to enable a link between clinical research and healthcare through standards. We strongly

encourage the FDA to continue its support of these standards development efforts which are critical success factors for translational research and electronic submissions and data exchange. Variation in terminology is also a barrier to effective collaboration, data aggregation and multidisciplinary research. CDISC collaborates with the National Cancer Institute in a number of ways, including the development of standards relevant for oncology. CDISC through NIH roadmap grants

in collaboration with Duke Clinical Research

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Institute has work under way to develop therapeutic area terminology standards with the initial focus on cardiovascular and infectious diseases. FDA should continue its

support of terminology standards. CDISC is leading a collaborative group devoted to achieving Critical Path Opportunity Number 45 to standardize case report form data collection consistent with the STTM format. FDA should provide

additional support to complete this work which will provide tremendous value to investigators, clinical research associates and monitors, project leaders and others who work at the front end of the clinical trial process. As mentioned earlier, these

benefits will cascade to provide significant downstream benefit for electronic submissions. It goes without saying that the infrastructure to receive standardized electronic submissions is critical. standards. However, the lack of an So are

infrastructure, its absence, is a barrier to standards development. We need a test bed.

We need to be able to demonstrate that these standards, once developed and implemented in our sponsor companies, in our member companies, will actually be acceptable to FDA. Therefore CDISC supports clinical

research information exchange as it's currently being proposed. Additional standards. Before

specifying additional standards, CDISC believes it is important to first apply the existing standards effectively and to work to harmonize standards to support semantic interoperability within clinical research and between research and healthcare. Significant

progress has been made in this area with the Biomedical Research Integrated Domain Group, or the BRIDG modeling efforts. initiated by CDISC. This was

It's now an open source

model governed by FDA, CDISC, NCI and HL7.

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Further harmonization support is needed in specific areas, including the following. To harmonize the multiple

standards related to adverse event reporting. At last count there were six. Clearly a

requirement of biopharmaceutical companies to report globally, having to do that in multiple formats is a problem. Doing

government-sponsored research and have to provide adverse event data in one form, why does it have to be different than industry? And I could go on and on. This is a

significant area of concern given the importance of drug safety and surveillance. We also need to complete - ensure compatibility with implementations of the CDISC HL7 protocol representation standard, including trial design. Further, we need to

harmonize the protocol representation standard and SDTM with the needs of other regulatory agencies and global organizations. For example, EMEA's EudraCT and the WHO's International Clinical Trial Registry

Platform and various results reporting projects, all of these need to be harmonized so that we can adopt the standards to be more robust to meet the multiple needs of these different stakeholders. Global pharmaceutical companies will appreciate the efficiencies they will gain if there is harmonization of requirements and a single consistent set of standards used across multiple groups such as FDA and I might add within FDA. It's

important to - if there were clarity and consistency within the agency and I know that is a priority. Also with EMEA, WHO and NIH.

These groups are requesting trial registry information and results reporting subsets for multiple purposes. If these data formats are

designed to support semantic interoperability there will be cost and time savings for all stakeholders globally. important. This is very

We ask that FDA recognize and

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support CDISC's continued leadership of these standards enhancements and harmonization efforts. CDISC supports the use of a third party entity, especially if that accelerates the decision by FDA to require electronic submissions in a standard format. We believe

that the benefits to patient care and all stakeholders far exceed the initial cost. CDISC asks that FDA recognize and support CDISC's continued leadership in these areas for the enhancement and harmonization of standards for clinical research. Thank you

very much for this opportunity to add our comments today on behalf of CDISC and its board and all of its members. We're very

grateful and now we'll take questions, and Wayne if you'll join me. DR. WOODCOCK: much. Randy. DR. LEVIN: First, I'd like to Thank you very

Are there questions from the panel?

thank the CDISC organization for their

efforts on moving the data standards forward. They've done a lot of good work and I appreciate all the work that you've been doing on this. One of the things that you

noted on your presentation were that some companies are being proactive but others are waiting for a mandate. Can you elaborate on

that, why they're doing that and what are the issues? DR. HARDISON: I'll make a general

comment and, Wayne, you can add some specifics. Implementing standards requires And I think that industry and

an investment.

especially this industry who's risk averse in its nature are waiting for an indication that, (a) this is an absolute requirement, and (b) the agency is actually ready to receive electronic submissions. the general comment. Wayne? I think there are a So that's

MR. KUBICK:

couple of other points as well that are

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relevant.

One is companies are concerned

that maybe the standards environment isn't terribly stable yet, that things will be changing, they'll be making investments and then they'll be forced to change again. so we need to have a uniform message that we're going to hold to these standards, they're going to be backward compatible and that work you put in now won't be lost in the future. I think the other issue which is pretty important is that it's a very complex standards environment. A lot of people are And

looking out there and concerned that there's competition between some of the standards, the HL7 versus the CDISC standards for example, and we're working very closely to keep those harmonized. We're working very But

tightly within the RCRIM environment.

the perception out there is not quite as clear. And so there are concerns that again

something else will come along right after I've gone, put the effort into implementing

what's there now.

And that's one of the

messages we need to get across is a uniform stable standard that we're all supporting, we're all working on the same direction. DR. LUTTER: Thank you. Could I

just follow up on that mandate question that the other Randy asked? And that is do you

see that as necessary or would alternatives such as incentives, think reductions in user fees or maybe changes in performance goals or options like that might also be an appropriate substitute for mandates? the first question. The second one is in that same slide on key messages for management from the PhRMA-Gartner-CDISC project, could you elaborate more on the nature of the cost savings? In that slide you had an average What That's

per study cost savings of $9 million.

type of study is one where one might expect savings of that nature? Thank you.

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DR. HARDISON:

Okay.

I'll try to

address the first question around incentives versus mandate. Basically I think that a

number of companies who see the benefits of implementing the standards upstream in the whole lifecycle of clinical research at the beginning around - even with the protocol and especially when they're designing their data capture approach, the case report form annotation, data management plans, statistical analysis plans. Companies just

see the benefit of doing that according to consistent standards globally. say well which standards? CDISC standards. sense. And then they

Well, there's the

It just makes good business

So a number of companies no matter

whether FDA ever requires or mandates electronic submissions in the standard format, you just see the business benefit of moving to the standards. So a lot of

companies do not need a mandate for that. Then there's whatever proportion, I can't give you an exact calculation of

this.

A number of companies are - like to They're aware of the

sit on the fence.

standards activity, but they're waiting for a clear signal from FDA that there will be benefit from them making investments in implementing these standards. So what

signals do they have that this is going to be something that is worthwhile? One, clearly

having reference to the standards and specifications in guidance documents is a good step. Mandate versus incentives, I can't answer that since I'm not a sponsor company, but when I used to work for a sponsor company clearly incentives are good because the cost of drug-to-development is so high. So

therefore I would think that it would be a driver. But there's still nothing short of

being able to point to a rule that says, you know, you must do this if you want to get your new drug application approved. The

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strength behind that I think outweighs whatever you might be able to do with incentives. Now, the other question, second question. that? Do you have anything to add to Second question, around the The

Okay.

Gartner-PhRMA-CDISC business case.

savings - problem with doing any kind of business case industry level and also being trained as a statistician early in my career, you have problems with averages. The

average, that number, the $9 million savings, was based on average IND clinical trials as reported by - I think we used CMR data as one of the primary sources for this. Then we

also used Tufts data who estimate that the average - once again, average cost of drug development is I think $37,000 a day. So

when you look at the - and the folks that participate in the business case study, major biopharmaceutical companies who have adopted CDISC standards. We were able to extrapolate

the savings that they accrued down to the

average investment required for clinical trials to come up with that $9 million on average savings. So typically these would be

the large multi-center clinical trials, pivotal studies, Phase III is where you would start to see that amount. Smaller studies

you'd accrue less savings, bigger studies more savings. Hope that helps. Ken.

DR. BUETOW:

So I think several

speakers - and again, you all have acknowledged this challenge of both ambiguity and inconsistency of the current collection of standards. And in a certain sense we find

ourselves maybe caught in this sort of chicken and egg sort of universe right here as acknowledged by you all as people don't want to adopt the standards until they're stable and harmonized, yet we don't have harmonized standards. So can you help us see

a path forward that we could very rapidly get to harmonized standards that seems like a

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prerequisite for this? DR. HARDISON: I'll let Wayne

answer this after I just make one general comment. It's that we've got to clarify

first, when we say "harmonizing standards" be clear on which standards we're talking about. And the second comment is within those standards that CDISC are producing, it is a number one priority to make sure our standards are harmonized internally. And

from the board's standpoint we've invested significant dollars to put, you know, put something behind our words. And Wayne is

leading that effort and can say more about that. MR. KUBICK: different points. There's a couple of

I think first of all

different standards represent different constituencies and so the more broader you make the scope the tougher the problem becomes. Within CDISC when our original

scope of supporting standards that support regulated clinical research among the

commercial pharmaceutical industry, I think we feel our standards are pretty solid. There's work to be done to tie them together, but we think they're usable and that we're committed to making sure that there's going to be a clean, upward migration path for any work done forward. The second part of the issue is harmonizing with the broader world and we're working together with NCI and with HL7 RCRIM on the BRIDG model, the bioresearch information development group, domain group, the BRIDG model. And we're making sure that

we're representing all the standards and the semantics for all the standards and the semantics for all the standards in this common domain analysis model. We've been

very successful to date without having to really make any structural changes to the existing standards, but making sure that we make the interconnections between them. That

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really is a critical centerpiece moving forward to make sure these activities stay harmonized. DR. BUETOW: Maybe a riff on that

same thread then and it goes back to the early question of mandate versus consensus or incentivize. Would you argue then there's a

strong role for mandating specific standards for the deployment and then other things will harmonize or lock in around those? DR. HARDISON: Well, selfishly,

mandates are always good for standards development organizations. MR. KUBICK: But a mandate doesn't

necessarily have to take the form of legislation. A mandate that, you know, we

need this in order to achieve our principal mission of delivering better healthcare to the world and ensuring patient safety is a strong mandate. If we keep that consistent

message and make sure that the right things to do in support of that mandate I think we can make a lot of progress.

DR. HARDISON:

And if I may add,

that's why having an organization of public/private partnership that provides an environment for actually demonstrating the efficacy of these standards if you will is so critical. Because that then would allow us

to more rapidly pilot and move from the actual development of the standards to implementation of the standards in an accelerated way. DR. LEVIN: I have another

question if I could, going back to when we were talking about the timelines on investment. bit? Can you expand on that a little Can you say a

How would that work?

little more, like if you're going to now go in to adopt a CDISC standards, move it into your system just at a company level, what are the timelines that are associated with that? Or how is that? DR. HARDISON: Well, it depends

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very much on the size and complexity of your organization, your legacy environment versus you know a small startup biotech where you have a green field. So it's going to vary

tremendously depending on your starting point. Now, Wayne, you've been involved with Do you want to

several implementations.

comment specifically on that? MR. KUBICK: Well, I think again

partially as a consequence for some of the other issues we said earlier, a lot of companies have been adopting standards pretty much at the end stage process. You know,

taking what you get out and mapping it and that's seldom an effective way to do things. The critical issue is moving things upstream. And it really isn't necessarily a huge issue if you start out with the standards embedded. I think the problems we have is sort of unlearning the years of legacy processes and individual standards that have been done. Some companies make the transition very quickly in a matter of months. Others,

larger companies certainly take longer times. You know, that's the transition implementation path that has to be followed. DR. LEVIN: If you're starting off

with a new study, I mean that would be the easiest transition, I guess. MR. KUBICK: DR. HARDISON: Absolutely. Yes. I have

clients that I've worked with who, once they made the commitment to the standards, they required a mandate in their organization that said all new studies starting January 1, 2007 will use the standards. And then you have to

make a decision well what about ongoing studies. Given where they are in their

lifecycle, is it cost-effective to convert them or not? And you know, that's just a

business decision that you have to make on a study-by-study company-by-company basis. DR. WOODCOCK: much. Thank you very

Our next speaker will be Mr. Tom Klaff

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from Surety. MR. KLAFF: I want to thank you

all, especially the panel for letting us speak today on the electronic submission standard and what Surety's perspective is on this. My name is Tom Klaff. I'm the CEO of

Surety and we are a trusted third party timestamping company. notary. Some call us a digital

And I stand here to represent not

just my company, but also an industry, a burgeoning industry called the trusted timestamping market. And only about three years

ago it really didn't exist, but as many folks who are familiar with record management and migrating from paper records to electronic records and also through what's happening with the Federal Rules of Evidence and the Federal Rules of Civil Procedure, the need to prove integrity of data is really very important and especially when organizations rely on this electronic information that constitutes roughly 70 to 80 percent of their asset value, it's very, very important.

What I want to talk about today in a very short time is just give you a brief introduction about who we are and then go into some of the obstacles faced by going all electronic. this. We have a lot of experience with

We have several customers who have

made this decision or are making this decision and it required the need to prove independently of their people, processes and systems that all of their electronic records and forms and meta data and audit logs had never been altered either maliciously or inadvertently. I want to talk about also

from the perspective of a third party provider. I know part of the submission

standard is who would be able to provide this kind of service from an archive standpoint. Surety has a lot of experience working with third party archive service providers because it attacks a wholly different problem. you're a custodial data provider, you're When

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managing other people's electronic records and there's a need to mitigate that risk and to prove legally that during its chain of custody those records were never maliciously altered. I want to talk about the industry

standards surrounding trusted third party time-stamping and as I indicated before, I am also a representative of what's called the Information Assurance Consortium which is a body of time-stamp vendors who have come together to form a standard working with the American National Standards Institute, ANSI, in what's called the ANSI X9.95 which is endorsed by many of the financial service companies that you know today including also NIST and NSA. And then lastly I want to just

give a brief implementation scenario about how this would work inside of a live customer. So Surety is an IT security software and services company. We're based

in Herndon, Virginia and we provide software and we operate a third party trusted time-

stamping service called AbsoluteProof. AbsoluteProof enables our customers to protect and defend their intellectual property by independently proving the integrity of their electronic records from the point that they were created ongoing for permanent preservation. The issue that we're

addressing as part of third party trusted time-stamping is legal defensibility. And

underneath the legal defensibility angle there's intellectual property protection and litigation readiness. Many companies we work

with in the life sciences market have made a conscious decision to move from a paper-based record management system to an all-electronic records management system. Some have Some are

deployed electronic lab notebooks.

going with electronic records management systems and building their own custom applications but in each instance they've all recognized the need to integrate the ability

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to prove that their documents, their electronic IP was pristine. And especially

when it comes into litigation, and especially considering the recently amended Federal Rules of Civil Procedure. During meet-and-

confer sessions those files could be turned over in electronic record discovery and there is a need also from the electronic file standpoint to prove that those haven't been altered. important. A number of reasons why data integrity is a specific issue. First and So authenticity is very, very

foremost about 93 percent of all business records today are electronic. And everybody

considers the outside attacks being a clear threat to infrastructure, and clearly it is, but what people don't realize for the most part is that for the most part, 60 percent of IT security breaches happened inside the enterprise with trusted insiders. And those

are the databases and the record management systems and the electronic assets that are

really very, very important.

Also with the

advent of more publishing software it's very, very easy to tamper with electronic records if you are an insider, but very, very difficult to detect the manipulation of those records. And lastly as I indicated, data

integrity is really a key component as part of anybody's electronic vital legal defense if they're going electronic, and that's going to be a very, very important issue to consider going forward. So what does time-stamping provide? Well, it's really an added layer of

assurance to what companies are doing in the electronic world. Clearly we're not talking

badly of electronic signatures or digital signatures. We're looking at this as really

an addition or an additional layer of assurance because at the end of the day digital signatures could expire, they could be compromised. There needs to be a

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cryptographic binding of an electronic record with a secured audible time source and that's what we're advocating. So really from the

standpoint of trusted time-stamping it's the what and the when in addition to the who that makes a very compelling argument to defend legally your electronic records. Lastly, there's a need to prove irrefutably that those documents that you possess, those forms that you are archiving and managing are trustworthy. Sandra Lambert

who was the editor of the X9.95 standard, quote, says, "Trusted time stamps will replace mechanical, manual or systemgenerated time stamps and provide a tool that will offer an evidentiary trail of data authenticity." Anybody that has a laptop

knows how easy it is to turn back the date and the time on your laptop. And we have

several examples at Surety where we can demonstrate that even with a PDF file with a backdated time clock and a digitally signed document for that matter can actually show

that a record that existed - even an article from the Wall Street Journal that was published on January 17 could be signed by somebody with a digital signature on January 5 and then validated. So from a legal

standpoint that is a clear piece of evidence that could be challenged and could be thrown out. So why do customers choose our service? One, and first and foremost really

from the life sciences standpoint and from the semiconductor industry and the manufacturing industry and the aerospace industry and even the government is to be able to prove that your intellectual property is yours. It's an effective deterrent with a

time-stamping service integrated into your business process to deter others from actually going in and manipulating electronic IP. Secondly, it's the ability to really

monetize the value of going fully electronic.

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A lot of organizations go halfway. them hybrid.

We call

They actually want to go

electronic but also use paper printouts as a way, as their redundant record management backstop. And really that is a very costly So the ability to prove

endeavor indeed.

non-repudiation is important and with having the ability to attest the integrity of that document similar to a wet signature is really, really important. We talked about legal defensibility and authenticity and then the ANSI X9.95 standard is what I want to get through next. AbsoluteProof application

areas, other time-stamping providers can actually seal any sort of data. It could be

Word documents, PowerPoints, it could be audit logs, meta data, it could be audio, video, it really doesn't matter. At the end

of the day it's asset data that is important to the end user. And if it's important to

the end user, it needs to be protected. From a third party service

standpoint if I am an archive service I need the ability of three key things. One, I need

to have the ability to have long-lasting protection because if I'm managing a lot of infrastructure, there's no question that my infrastructure will obsolesce over time. It's the ability to constantly upgrade that environment and know that the records that are being managed and stored will not lose their ability to be proven authentic. Secondly, it's the ability to be independently verifiable. And when I talk

about independent verifiable, I mean independent of your own customer's people, processes and systems and of yours. all could be challenged legally. And lastly, it's the need to go with standard solutions, and that's what I want to talk about now. The ANSI X9.95 So these

standard is a standard form for trusted time stamp management specifically endorsed by the

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financial services community.

It was

unanimously approved back in 2005 and it allows for choice. There are a number of

technologies that at one point were proprietary and now they are part of a standard so that there is vendor neutrality and the ability for customers to know that their investment is protected in time stamps. Under the standard there are four specific technologies that are proved and endorsed. One is a digital signature type of timestamping, two is a message authentication code, three is link token, which is what we do, and the fourth is transient key. And

within the standard there's a comprehensive set of processes, procedures that would allow organizations who wish to deploy these time stamps to be complicit. We are often compared to an RFC 3161 standard which really technically isn't a standard. It's just a request for comment.

But the X9.95 trusted time stamp standard does include digital signatures which RFC

3161 supports, plus the other three techniques. What's also key is that there is

policy and practice statements involved in the standard. There's audit evaluation

criteria and the process is well spelled out, including time calibration and auditability of those time stamps that come from secure sources. With the last remaining seconds I have left I just want to go through an actual implementation scenario where an organization has migrated from a paper-based record management system to an electronic record management system and has used a third party time-stamping service provider like Surety to seal and validate the integrity of their electronic IP. And this happened to be

integrated into an electronic lab notebook infrastructure also using electronic signature. So from really the concept of the

idea until the preservation of the idea there

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is a seal that is assigned to that specific file. That file can be stored in any record And then at

management or archive module.

some point in the future if that file or if a patent or a trade secret is being litigated, that piece of evidence can be sent along with the trusted seal to a third party for validation. So the key point here is that

it's very, very important when considering electronic submission systems and management systems that you consider the legal defensibility angle and know that down the road 10 - 20 years from now when challenges do occur and the people who were originally there aren't there anymore that those records have the ability to stand up in court. In conclusion, there are a number of ways that you can go about doing this. We

believe that as organizations go through the electronic record management process and decide for themselves that paper isn't necessarily the way they want to go, that there needs to be a mechanism in place for

being able to prove the integrity of their electronic records. And Surety's

AbsoluteProof time-stamping service is one of those mechanisms. And we've been able to

work with organizations who wish to protect their IP, but also organizations who from a third party standpoint wish to mitigate their risk and be able to prove the chain of custody has never been altered. DR. WOODCOCK: much. Thank you.

Thank you very

Are there questions from the panel?

Yes, Kevin. DR. FAIN: question. Yes, I have one

I was interested in you mentioned

that the time stamps have been used in the context of private litigation for authenticity of documents. I was wondering

in terms of FDA and FDA inspections, are you aware of those time stamps being considered or used by companies, especially when FDA is inspecting records? And I guess a follow-up

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question to that would be are there any unique issues for FDA to take into account in considering these time stamps? MR. KLAFF: Well, I think that I

mean from our company standpoint we haven't engaged with the FDA in any sort of commercial endeavor. But I would add that

the time stamp technology that we use really is - if you're familiar with secure hash algorithms, they're NIST-approved so there isn't really anything proprietary about them. From a litigation standpoint typically technologies aren't challenged as much as the processes are challenged. So from that

standpoint all we're doing is we're helping organizations who have specific processes in place know that in a litigation standpoint you can surely challenge their processes, but when it comes to the actual data there is irrefutable proof that nothing has been changed. And we're advocating that if you're

looking at standards from an electronic submissions standpoint, you might want to

consider the ANSI X9.95 standard. DR. WOODCOCK: from the panel? Any other questions

Thank you very much. Thank you. Our next speaker is

MR. KLAFF:

DR. WOODCOCK:

Nancy Smerkanich and she is Vice President, Regulatory Affairs, Octagon Research Solutions. MS. SMERKANICH: Thank you Dr.

Woodcock, members of the panel for first of all for pronouncing my name right. get that very often. I don't Thank

I appreciate it.

you for allowing me to speak today.

A little

background about myself and why I wanted to present today. I've been a regulatory

affairs professional for 20-some odd years. I started off my career in big pharma. I

worked as an independent consultant and for the last six years I've been at Octagon. My

primary responsibility in all that time was compiling and maintaining both

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investigational and new drug applications. am certainly not only a believer in electronic submissions, but probably some people would consider me a bit of an evangelist about them. I spent the first 10

I

years of my career saying there's got to be a better way to do this and then I found the better way and I want everybody else to do it that way as well. For purposes of full disclosure I should tell you that I am working at Octagon. I'm not only an employee but a stockholder. And we are a software and services provider to the pharmaceutical and biotech industry, primarily focused on electronic submissions but also the data management and data integration that's involved in creating those deliverables for electronic submissions. the benefits may seem obvious to you if electronic submissions become mandated, but to me it means I get a whole lot busier. I'm already very busy. But the most compelling reason And So

that I asked to present today has to do with the fact that we sent an email blast out of all of my regulatory contacts which numbers between 200 and 300 people about this meeting because a lot of people have trouble keeping up to date on the docket and so we sent out the email blast and the response to some very simple questions that were in that email was overwhelming. In addition to the responses

to what I'm calling an informal survey, I received numerous voice mails, emails, people even tracked me down on my cell phone to ask me to present information on their behalf today because especially for small to midsized pharma there's a lot of regulatory people who wear multiple hats who knew they wouldn't be able to attend today. So while

there were many great questions I think in the docket I'm going to confine my remarks to transitioning to and implementing electronic submissions from the point of view from these

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responders.

Hopefully I'll be able to answer And

some questions from my own experience.

then there was also a number of questions in the docket about cost and time of doing electronic submissions so I have a couple of scenarios that I can present to you. Hopefully you'll find them useful. They

involve not only the cost of the production to do an electronic submission but also the time involved. So we took the questions in the docket and kind of boiled them down to a little bit leaner, meaner set of questions basically asking folks have they implemented electronic submissions within their organization and if the answer to that was no, why no. And then asking those who had

what were the major challenges of implementing electronic submissions and what were the major benefits. And then

specifically trying to get at some of the concerns around cost we asked if those costs associated with doing this was burdensome.

And then we left the field open for additional comments. And I have to tell you,

you'll see in the next few slides where there were some people who didn't answer any questions but wildly used the additional comment field. those as well. So I've tried to summarize So I received 77 responses in

seven days plus all the emails and the voice mails. So this is obviously a hot button The

issue for a lot of folks out there.

companies represented were either tier one big pharma, tier two you know kind of midsized pharma or small pharma as well as some additional participants who represented CROs, medical devices and vet meds. And then the answers were kind of split amongst have you implemented electronic submissions within your organization. are overall percentages. The tier one These

companies, 10 yeses, they equated to 13 percent, six nos. The tier twos were split.

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The tier threes had 26 companies that had and 28 that had not, and the others were split equally amongst them as well. So when we asked the nos why no, why haven't you done electronic submissions, some kind of interesting information perked out of this. For tier one companies they

cited lack of internal resources and expertise, lack of upper management support which in big pharma is an endless chain at times. They cited costs and they cited And I think a number of

ingrained processes.

people today have addressed the fact that big pharma can be very hard to move to a new way of doing things. change management. It has a lot to do with Tier two companies were I

both undergoing pending acquisitions.

don't know if that was of their companies or of their drugs, but it certainly puts you into a holding pattern if you don't know what your future is going to be. As for the

little guys, the tier threes, they cited time, costs, expertise and resources. And

again, we'll get into a little bit more about what I think time, cost, expertise and resources mean, but in fact a number of them were in the stage of assessing how to go to electronic submissions and a number of them were also implementing. management constraints. They too had The fact that

electronic submissions aren't mandated was definitely a barrier for some of them. of them it was just an issue of timing. Some They

didn't actually have a major submission that would warrant it. All of the companies that

were in the ancillary area were in the implementation stage so I think that's encouraging. And as I mentioned, you'll see It just means they went

34 no responses.

directly to the comments field. So for the folks that had gone to electronic submission we asked what the major challenges were. And you'll notice that tier

one and tier three have identical responses,

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but I think it has a lot to do with what time means to big pharma and what time means to a smaller company. Time to change existing

process to integrate with numerous other tools for big pharma and lead time for small pharma. Just having that built into their They both cited cost.

development process.

Again, cost if one of those things, for big pharma it's a lot like renovating an old house, but for new pharma it's like new construction, and there are a lot of costs associated with both. The fact that both

cited expertise I think is interesting and it kind of speaks to where the workforce is and where the experience level is with electronic submission. Training, obviously very important and resources. And I think a lot of time

resources for a small company can mean everything from an IT infrastructure to an IT support person as opposed to dedicated resources in a bigger pharmaceutical company. Both cited process change, but again I think

they mean different things.

I think for tier

one pharma you truly are talking about changing existing process, but for smaller pharmaceutical companies you're talking about no process most of the time. There were some technology issues cited by the tier two companies and some additional things for the tier threes which was they just didn't even know how to create compliant documents and didn't have document standards. They dealt with a lot of legacy

study information and again, probably most of it outside of their control. And that they

couldn't communicate to the management that these challenges could actually be timeconsuming and costly. The major benefits. Really they

validate everything I've been saying for the last six years so I really am happy to present this slide. Both - actually across

all of the companies the major benefits of

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electronic submissions were seen to be the ease of use within the organization, the speed of compilation. As one of the end

people it is faster, but it isn't a push of a button. Compatibility with other systems was

very important for big pharma as were harmonization mostly across sites and across subsidiary companies, reviewer friendliness and document reuse. I love the fact that all

three tier companies said no paper because that certainly was recognized as a benefit. And it was interesting to me that the tier one companies perceived that there was a quicker agency approval with electronic submissions although we've never been given any metrics to that effect. Dr. Levin when I say that. I'm looking at For tier three

companies again they stated that the same benefits and so I think there's a real consistent message there in terms of what are the benefits. In response to the question about costs it was a very interesting split here.

Tier two companies you'll remember from the last slide were the ones that had technology issues and they clearly felt that there was a burden to the cost of implementing electronic solutions. But tier one and tier three

companies were relatively split amongst them as were the others and the others were actually more favorable in terms of there not being additional cost burden on creating electronic submission deliverables, but I suspect that's because they were from CROs and so they basically have electronic databases and electronic documents so they weren't implementing a whole enterprise-wide solution. Fifty-one of the respondents provided additional comments, some of which were very lengthy. It was a good venting And

session for some people I have to say.

so to try to summarize them was actually a little bit difficult. But since everyone hit

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on cost I did make a point around summarizing that, that most if not all of the companies in some way or another cited costs as an issue but felt that the cost of implementing electronic submissions would be worthwhile in the long run. And I have to say I take this

quote and I'm probably going to reuse it again because it's a good one from a small company. "We build and collect things It makes sense to submit It's the cost of doing

electronically.

them electronically. business."

Some companies felt that the

impact of the costs actually hurt them in a competitive environment. And I think that

this comment also related to some issues that especially small pharmaceutical companies face when they have limited resources in terms of head count and they have to choose someone to place on the clinical team or someone to place in regulatory operations. Guess who usually wins? During the

development phase clinical usually wins. Some companies felt that finding the correct

technology that's reliable and current is not only an issue but will continue to be an issue. I remember one of the comments

actually said getting the right people and the right tools at the right time was probably their greatest challenge. And there

were at least seven if not more companies that responded that they really wanted to see ECTD mandated because it's the only way they felt they were going to get buy-in from their upper management and to move their contributors away from a paper paradigm. So

again, that's just a sampling of the survey results. Since everybody talked about time and cost I thought it would be maybe beneficial for the panel to see some time/cost information. It's based on an

outsourcing model because that's what I have access to and it's very important that the outsourcing model be considered as part of

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this because I think it is where all of the time, the costs, the resources and the expertise lie. You're basing these costs on

having a validated model, validated software, a pressure-tested process and emphasis on pressure, and a trained staff. And so making

sure that that's your baseline that you're using created a couple of scenarios around this, one of which is that you get all submission-ready documents. For people who

live in this world they know that's a bit of a dream, but content and format having been reviewed and approved upstream of you. It's

also assuming that documents and data are provided on a rolling basis. It's not this And for

giant bolus of work at the end.

Scenario 1 I used a smallish submission, SNDA, a small 505(b)(2), even an IND around 150 volumes with about half of it coming from an electronic source versus a paper source. And you can see that assuming that infrastructure is in place, electronic submissions can not only be cheaper, about 15

percent, but you can also do them faster. I created another scenario based just on a bigger submission but again on the same model and you can see that the total cost again for electronic ended up being cheaper, not as big a difference, about 11 percent. And also easier to compile, faster I want to hover on this slide

to compile.

just for a minute, though, so that everybody knows. This is not a cheap thing to do.

Either way you look at it you're talking about over a half a million dollars, and this combined with a user fee that's creeping up to around $900,000 is a tremendous amount of money for a small company. And so that was

one of the points somebody asked me to make and so if you consider some of the incentives, you may also just want to consider the overall cost. And this doesn't

involve any of the costs around doing any data integration or data standardization.

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So just to conclude and leave a few minutes for questions, the major impediments and the challenges kind of across the board have to do with time from different vantage points. there. Certainly there's cost

There is more expertise needed, but I

think there's also more expertise being gained. Training is always an issue.

Getting the same folks out to meetings and out to training can be difficult if they're wearing multiple hats within a company. Resources and I think process change is probably underestimated. But electronic

submissions has delivered on its promise in terms of major benefits, ease of use, reviews both internal and external, the speed and I think the one I'd like to highlight, the accuracy which people doing electronic submissions felt their submissions were better. And I think that's certainly maybe

the takeaway from this is that you know we have accomplished better submissions and so that was certainly the point of all of this.

So I have a few minutes left for questions. I do hope the panel found the information useful. DR. WOODCOCK: much. Levin. DR. LEVIN: presentation. Thank you for that And Thank you very Randy

Questions from the panel?

It was very helpful.

thank you for all your help in electronic submissions over the years in all the different venues. You've been doing a lot of

work to help people move to electronic submission so I want to thank you for that. MS. SMERKANICH: appreciate that. Well, I

The template of the slides You can find it.

now is called Levin-esque. DR. LEVIN: of color in this slide. MS. SMERKANICH:

There's a little bit

Well, there is.

More than you would have liked I would imagine.

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DR. LEVIN:

The question about the

cost and going back, and what about implementing over time and reducing your cost? How does that work or can you expand

on that a little bit? MS. SMERKANICH: Well, since a lot

of the cost is based on implementing the software, a lot of times that's going to be a one-time cost so this is kind of taking that out of - this is truly just costs around production, doing the reviews, doing the post-production changes. same consistently. So it would be the

In terms of time and cost

to implement the software and the people and all of that, there's a lot of variables that go into that and it changes from whether you're a small company with a blank canvas to a big company that has a lot of systems to integrate, certainly. DR. WOODCOCK: DR. LUTTER: Randy Lutter. Could you go back to

the time and cost Scenarios Number 1 and Number 2? I'd just like a little bit more

clarity if you would about exactly what these numbers are supposed to describe. the costs of preparing an NDA? MS. SMERKANICH: Yes. Two These are

different size NDAs from the point of where the documents are ready for if you want to call it the publishing step. And electronic

in this case was both - an average actually was almost a wash of doing an electronic NDA with PDF tables of contents versus an ECTD. It was pretty much a wash with that. DR. LUTTER: So excluded from this

is any improvement in interactions with FDA as a result of having submitted an electronic document as opposed to a paper document? MS. SMERKANICH: Yes, actually we

did have a minor couple of lines in there about the ability to answer questions from the agency based on a paper submission and the ability to do re-analysis. And clearly

those are what bumped up the paper costs

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because they tend to be faster and quicker and more efficient interactions with the agency if you do have both the SAS data sets in the proper format as well as the electronic submission with all the navigation. So we did include that, yes. DR. LUTTER: DR. WOODCOCK: Armando? DR. OLIVA: Is there anything Thank you. Other questions?

upstream that the company could do before publishing or coming to you for publishing that would help reduce these costs, either paper or electronic? MS. SMERKANICH: Yes. I think

that's an excellent question and I think a number of the speakers, especially the gentleman from CDISC have addressed that. mean, the more standardization that occurs upstream in terms of the data and the documents, the more efficient the downstream process. And so you see companies that have I

good standards, employed standards, standards

that everybody has trained on.

They can

actually create submissions a lot faster than companies that have to go and re-map data or start with documents that have, you know, no consistent field. But having said that, all

of those upstream costs aren't even in these scenarios and they can be considerable as well. DR. WOODCOCK: DR. BUETOW: Ken? So from your

outstanding boots on the ground experience here, what would be some critical things we could do to facilitate this? So in other

words, obviously you're an evangelist, so what are, you know, what is keeping you from proselytizing at this point? MS. SMERKANICH: keeps me from proselytizing. Well, nothing A lot keeps the

message - well, I mean a lot of it is this is perceived to be a nice-to-have I think by a number of people. So when you see tier one

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companies saying they don't have upper management support, that speaks to me that this is perceived as a nice-to-have. I think

again to speak on behalf of the people who I claim to be here for, there are so many small companies that their focus is - it's a day to day thing. It's get this study done. It's

get my database clean. locked.

It's get my database

It's get my tables and listings, you And for them to see the big

know, done.

picture and to see the end product, sometimes they don't even consider it until they're sitting at the pre-NDA meeting and someone says to them, well, is your data going to be in CDISC format or is it just going to be an electronic submission. So a lot of times They

it's a matter of priorities for them. have to spend their money wisely.

So much

drug development is being done at such a lower level now than when I started it's amazing to me, and those people have a totally different focus. They're focused on

the drug discovery and the development piece

and they're not necessarily thinking about the marketing application. DR. WOODCOCK: DR. LUTTER: Randy Lutter. One follow-up. These

data give such a compelling argument for industry to submit electronically. MS. SMERKANICH: have that top piece. DR. LUTTER: paper. Rather than via As long as you

What additional action do you Are there

recommend for FDA in particular?

mandates or incentives that you think we should provide? MS. SMERKANICH: I think that, you

know, again I'll kind of echo what Dr. Hardison said, that incentives I think for small companies probably hold more weight, but mandates for bigger companies hold more weight. I think that also in terms of just

communication issues, knowing that the FDA was 100 percent all review divisions,

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reviewers behind this would also help a lot because there still is this fear out there that, well, my reviewer doesn't like this, my reviewer likes paper, my reviewer isn't going to use the data sets. So I think if we can,

you know, that's certainly - that's an easy win as far as I'm concerned, but then they're not my thousand people, so. DR. BUETOW: Just real quickly.

So other than communications, are there barriers? I mean because again, as someone

said there appears to be from a cost model, you know. MS. SMERKANICH: pay one way or another. DR. BUETOW: It's a no-brainer. You're going to

So what other barriers would you perceive actually as a person who's literally doing this that are actually slowing this down other than communications? MS. SMERKANICH: think it's knowledge. All right, I

I think if more people

saw what they look like at the end, and

especially with ECTD, which is my new thing I'm evangelizing. If they saw the long-term

benefits of starting their INDs in ECTD and moving forward with them I think that they would, you know. And the fact that I think that's one of

redundancy goes away.

the things that has driven me absolutely insane over the years is the amount of redundance in the information that we submit. DR. WOODCOCK: Other questions?

Thank you very much for mounting that survey and presenting. MS. SMERKANICH: DR. WOODCOCK: You're welcome. All right. Before

I introduce our final speaker of this morning I would like to reiterate and ask people please do not wander off into the office suites here, okay? We don't have a facility

that's secured, you know, between the public access and our employees. So please stick to Our final

the halls and so forth, okay?

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speaker this morning is Mark Scheineson who is with Alston & Bird, LLP. MR. SCHEINESON: Mark? Good morning.

Again, thank you for the opportunity to present to this august panel. I'm

representing some of the little guys in proprietary and generic drug development. It's an honor to be back here with my former FDA colleagues. I'm going to try to go

quickly both because Nancy's presentation that you just heard was quantifying some of the points I'm going to be making here and because I'm standing between you and lunch. The goal obviously that all of us are discussing today is extremely laudable, especially if it expedites reviews and allows cross-application comparisons of safety data. I would like to just get to the bottom line and answer Randy's question or Dr. Lutter's question which is, you know, mandates versus incentives. From our perspective as

regulatory counselors to companies, we believe what's holding back a flood of

electronic information that's ready to go is a little bit of uncertainty on how to prepare those applications and uncertainty on how reviewers and uncertainty on how investigators or inspectors would handle that information and database. So from that

perspective, you know, any uniform standards or guidance that the agency could issue that helps specify some of those open questions as well as the prospect of quicker reviews and approval is enough to unleash a flood of electronic data. From the smaller companies' perspectives there must be recognition that the tasks involved in a transition remain daunting, especially for those smaller companies. Some of those tasks have been

noted before and are listed below in training and installation of a validated document management system that would be acceptable in GMP inspections as well as in regulatory

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reviews.

It's also difficult to find I think the little guys

qualified vendors.

are concerned that the experts in the field would be captured a bit by the bigger guys. And I think we've seen that whenever new rules are imposed or new requirements are imposed that finding the experts, whether it's, you know, NLE labeling or you know written pedigrees or RFID or other, you know, there are a limited number of vendors that are qualified and they quickly get inaccessible to the smaller guys. Other elements to consider are the large capital investment that is required to put these databases into place. Most of

these companies would probably utilize CROs to a certain extent to try to do some of this work of them, but not everyone can afford Parexel or Quintiles or some of the bigger, more sophisticated vendors. Additional There's

employees would have to be hired.

somewhat of a cultural shift that's necessary as was highlighted by management sign-off,

but once they hear that the best way to get an application reviewed promptly or quicker is electronic database, it wouldn't be hard to get management sign-off in our experience anyway. This is a cultural shift. It's

not unlike, you know, PDUFA for FDA and the changes that that made to a culture and to a methodology. key. Global harmonization is also

You know, if any standards that are

used can be global or harmonized that will be an additional incentive. And the benefits

are largely a bit in the future and not immediate. There's also a need for

universally acceptable standards as has been highlighted. It would be good that in GMP inspections that FDA would rely solely on electronic information. I know it's

important sometimes in the audit trail to see changes and deletions and things, but you

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know as all of us know that use Blackberries or email, I don't know if that's reduced the paper flow or people just make copies of their emails. And you know, that's a

lifeline that would have to be cut both at FDA and in industry. The deadline that was suggested, or a January 2008 date might be a little optimistic. I'm going to quickly review If

three issues and the thoughts of those.

it's mandatory especially there needs to be adequate transitioning, especially for those smaller companies that don't have the resources, but for large pharma as well. That just won't allow sufficient time for small and middle-sized companies to perform. As was noted, the cost for achieving electronic submissions is probably higher and more burdensome, at least in the short run. I think a lot of the responders

to Nancy's survey were polite in their listing of code words, like "expertise" or "cost" or "time." That "expertise" and

"cost" and "time" is probably on both sides of this transaction at FDA as well as in companies. And the pricing of these

services, especially if they're limited vendors that have that capability would likely be what the market will bear. that isn't going to be insignificant. And In

addition, you know for submissions that are already in progress there needs to be some transitioning and some transition rules to allow the scanning or converting or just use of the paper until new applications can be presented. costly. If the need to consolidate safety data is driving this, and that's very important to be able to look across applications, FDA might consider, and maybe it is already using this, some kind of standardized internal electronic reviewer software or checklist that could be utilized It's both time-consuming and

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that would draw together some of the data that the reviewers are compiling in their application reviews. That could be done

internally without any need for rulemaking or guidance. Secondly, time is an issue. The

timeframe must be realistic and should be based on outside research. And this kind of

Part 15 outreach is a first step in that regard. But there needs to be ample time to

hire consultants, to select the appropriate submission software, to ensure and validate its capability to roll out that software before the submission preparation can begin. You know, further delays could occur as I pointed out from just finding the right vendors. And of course for companies that

don't control it internally and some that do, they can't always control the timeframe and the priority that their submissions are given. FDA hopefully will meet with the

vendors regularly to evaluate and to motivate the process if it opts the mandatory route.

But new rules should be flexible based on the progress in the marketplace. So from the

perspective of these small companies, they believe that it should be no sooner than three years if there is going to be a mandate on which the agency - you know, three years from the time the agency issues a final rule or final guidance on electronic submissions. Last issue is seeking some sort of staged implementation. The agency should

allow for an ample implementation time. There should be a built-in phase-in period that's pretty specifically prescribed and the agency should consider accepting paper to accommodate those submissions. However, FDA

should ensure that equal treatment is accorded to the paper submissions during that phase-in period. Finally, FDA should ensure

that the electronic submission does not become a vehicle for requesting companies to include additional information or data beyond

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what's already required.

That was part of

the problem I think in the guidance that was issued for the original Part 11 is that you know, what records were covered by that guidance became a concern. So you've asked us a lot of questions. Some questions for the agency to

go back and consider I guess would be some kind of uniform specific software or systems for submissions that could be recommended. Uniformity obviously will ensure efficiency by streamlining your processes internally as well as the preparation of very complex applications. On the legal and regulatory I think it

side is what mechanism you'd use.

would be a lawyer's preference to use the rulemaking process, realizing how burdensome that can be, but it would be great to go to Part 11 and get all the information you need as opposed to digging up, you know, numerous guidance documents and other documents which aren't really binding anyway on either side. We also do believe that this is a substantive

rule in how it's likely to be structured as far as having standards and otherwise recommending uniformity. And in any

rulemaking there's always a small business assessment, and it would be great if this small business assessment could be based on consulting externally. Small businesses and

kind of not speculating on the time or resources that might be required. I remember

the HIPAA rule that we're all familiar with that said it would cost, you know, two days and $10,000 or whatever the cost would be of that methodology. Also, the question is how

can this be harmonized internationally the most quickly for companies that most of which market overseas as well as in the United States. Again, I thank you for the I'd be

opportunity to present these views.

happy to answer any questions that you have. DR. WOODCOCK: much. Thank you very Kevin.

Any questions from the panel?

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DR. FAIN:

One quick question.

I

was just wondering about the rulemaking option. Mark, if you have any thoughts about

are there some significant legal issues we would need to consider in writing such a rule? MR. SCHEINESON: I think you'll

avoid a lot of those issues by going the rulemaking route and a lot of, you know, potential litigation from companies that deem the requirements to be too burdensome that would delay the process. I think there are a

line of cases, Shalala cases in the late `80s that kind of had a 5-prong test of what it should include in the substantive area and why this kind of rulemaking would be substantive and not interpretative. you very much. DR. WOODCOCK: other questions? All right. Well, are there any Thank

Trying to get away from us. This

Thank you all very much.

concludes the morning session.

Again, please

restrict yourself to the hallways and doors

and so forth.

And we will reconvene and Thank you.

begin promptly at 1 o'clock.

(Whereupon, the foregoing matter went off the record at 11:56 a.m. and went back on the record at 12:57 p.m.) DR. WOODCOCK: All right. We'll

be having three presentations at this point and then we'll be having a break around quarter of 3:00. Our first presentation is I'm going to read

from a set of presenters.

all their names and they're going to do an ensemble presentation. Debra Bremer, Vice

President, Development and Medical Informatics at Pfizer. Diana McKenzie,

Executive Director, Information Systems, Amgen. Sue Dubman, Vice President of IT and Dr.

Informatics, Theravance, Incorporated.

J. Robert Beck, Vice President and CIO, Fox Chase Cancer Center. Advocate. Diane Paul, Patient

Bob Renner, CEO, Liaison And Mark Adams, Senior

Technologies.

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Associate, Booz Allen Hamilton.

They will

have about 45 minutes and we look forward to what they have to say. MS. BREMER: So in one of the

previous presentations they talked about a survey and summarizing the survey. We

brought all the survey respondents here. Good afternoon. My name is Debra Bremer and

I'm the Vice President of Development and Medical Informatics at Pfizer. And I do

thank you for the opportunity to speak this afternoon on clinical information exchange and electronic submissions, and especially in the most coveted time slot of the day. guess we drew the short straw. keep this moving along. I

We'll try to

Maybe that's another

reason for the presenters, we'll keep it flowing. And I'd ask respectfully that you'd

hold Q&A until all of us are done, our presentations, and we do believe we've timed it in such a way that we should allow time for questions and answers. So today I am presenting on behalf

of the CRIX community.

CRIX, which stands

for the Clinical Research Information Exchange is a secure shared technologies standards-based service platform. We are

developing this exchange to deliver valueadded services to the biopharmaceutical industry and for use in information exchange between research organizations or business partners and regulatory authorities although CRIX can potentially deliver similar services to support other regulated products. We as a community formed CRIX International as a not-for-profit entity just this month with the vision of a publicprivate partnership in mind. An entity such

as this is essential for the initial as well as ongoing success of a clinical research collaborative environment. The board of CRIX

International will be composed of representatives from both the public and private sectors and CRIX International will

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govern and oversee the operations of the services. While we've taken the initial

steps to form an entity that embraces a public-private partnership in its very structure, if desirable it could readily be merged into an existing strategically aligned non-profit organization. And I would say

that for more specifics on the role of CRIX International we have submitted to the public record for this hearing a CRIX executive summary document where you can get more details. We believe CRIX services will deliver to users workflow efficiencies, lower operational costs, reduced infrastructure development expenses and faster drug development times. CRIX can also contribute

to accelerated achievement of the goals of the FDA Critical Path and NIH Roadmap Initiatives. For example, a shared public-

private infrastructure provides a platform for streamlining clinical trials and potentially assisting with adverse event data

mining.

In later testimony you will hear

examples of exactly how CRIX can streamlining clinical trials. The CRIX community encompasses a broad range of stakeholders. Represented

within our community are hospital groups, patient advocates, government agencies, academic research centers, trade and standard-setting organizations and industry service providers. The CRIX community is

constantly growing and our goal is that it will embrace all organizations involved in supporting or overseeing clinical research. CRIX is a collaborative shared technology exchange. So it is fitting that

it grew out of two previous collaborations. Both of the preceding collaborations were looking to enhance and accelerate the process of developing diagnostics and therapeutics. In 2003 FDA and NCI initiated the Interagency Oncology Task Force, the IOTF, to streamline

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the development of cancer drugs.

In 2004 the

IOTF focus expanded to include a shared technology information exchange. At around

the same time the PhRMA trade association was engaged in an effort called SEBIX, exploring how to save time and money through the development of a shared infrastructure and means of information exchange. Last year, NCI launched CRIX as an initiative to demonstrate the value of a shared infrastructure, leveraging the momentum of the IOTF and drawing on lessons learned from the SEBIX experience. Development then began on the first service module for CRIX, the Federal Investigator Registry for Biomedical Informatics Registry Data, which is why we call it FIREBIRD. To

date, FIREBIRD has been developed under NCI's Center for Bioinformatics with knowledge, technical expertise and resources contributed by the broader CRIX community. Going

forward, we propose FIREBIRD as well as future service offerings be developed and

overseen by the formal public-private partnership represented by CRIX International. The CRIX community is active and thriving with broad stakeholder group representation. The community holds the

shared goals of lowering drug development costs and speeding new therapies to patients. We believe that an information exchange such as CRIX is essential to achieving those goals and we believe that CRIX has the financial backing, organizational sponsorship and the right governance and operation structure to make it succeed. We have demonstrated that

an exchange can work through the FIREBIRD pilot and we propose to release the production version of FIREBIRD in 2007. With

the governance structure that we're putting in place through CRIX International, we are confident that CRIX will continue to grow its services within clinical research and could

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be extended to support other regulated products. CRIX will continue to grow its

community and deliver value to community members and patients. Next, members from the stakeholder community will provide their perspectives on the challenges of drug research and development in the current environment and the value of a third party information exchange in addressing those challenges. They will also provide information which supports CRIX as an ideal model for regulatory information exchange and collaboration. Six speakers will give their

insights on CRIX, each bringing a different perspective on the need for, benefits of and governance structure of CRIX. We'll hear the

viewpoints of representatives from large and small biopharmaceutical companies, academia, the patient advocacy community, a provider of exchanges and an external industry sector as well as a service vendor. Thank you and I

will now hand over to Diana McKenzie from

Amgen who will provide the large biopharmaceutical company perspective on CRIX. MS. MCKENZIE: Good afternoon.

I'd like to thank you for the time to speak this afternoon also on the value that we think CRIX offers to the broader research community and to Amgen in particular. name is Diana McKenzie and I'm here to represent Amgen. Amgen is a leading human My

therapeutics company that serves the needs of millions of patients worldwide. We strive to

be an entrepreneurial science-driven enterprise dedicated to helping people fight serious illness and we believe that by aligning with the CRIX Initiative we demonstrate our commitment to this aspiration. I believe we are all familiar with the industry challenges we face in addressing both the costs and complexity of research and

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development.

In addition to these, Amgen has

experienced significant and positive growth over the course of the past several years. In light of both these industry challenges and our own growth, we are required to find ways to improve our business processes and our supporting IT infrastructure so that our increased scale does not slow progress with developing important therapies. These

improvements will help us to reduce the cost of clinical research in an effort to maximize both our investment in identifying new therapies and making those accessible to patients. FIREBIRD serves as an excellent example of the type of improvement that not only addresses challenges for the broader clinical research community, but also has value for Amgen internally. We expect that

with the successful deployment of FIREBIRD as displayed in the slide here we could reduce the cycle time associated with capturing the 1572 NCV during investigator site initiation,

which is a common industry process, from eight weeks to mere hours. In addition, we

believe that these reductions in cycle time also lead to higher quality information and improved ease of review for our regulatory colleagues. Lastly, we recognize that for

our investigator community we demonstrate our commitment to easing the administrative burden for them with participating in clinical trials, thus allowing them to focus on the patient. Our internal business case for FIREBIRD, while conservative, demonstrates the proposed reduction in clinical trial costs at Amgen for both the current phase, which is limited to the 1572 and investigator CV, and future phases where we expect to see greater return when expanded to encompass the entire site initiation packet. We have not

incorporated additional CRIX capabilities such as the patient recruitment matching into

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our business case, however we believe that these capabilities will only increase the value of CRIX to the research community. In summary, we believe that CRIX is an effort, one of many being pursued in the area of health information technology deployments which benefits all stakeholders. I've had the privilege of working in this industry for 20 years and I have learned a great deal about what it takes to successfully deliver IT-enabled solutions within research and development. I have been

actively engaged in discussions to advance the exchange concept since 2003. It is

because of the diverse CRIX community represented here today, the quantifiable business case we have developed and our collective desire to ensure all stakeholders benefit in some way that we believe the CRIX Initiative can successfully help us to address the rising challenges of speeding new therapies to patients and reducing the cost of research to maximize their access to those

therapies.

Thank you.

I would now like to

turn the presentation over to Sue Dubman from Theravance who will provide the small biopharmaceutical company perspective on CRIX. MS. DUBMAN: little. So I'll lower this a I would like

I used to be taller.

to thank the FDA and the NIH for the opportunity to speak here today. My name is

Sue Dubman and I know quite a few people in the room. I was actually one of the

originators of CRIX when I worked at the National Cancer Institute and have been a supporter of the need for CRIX from its early beginnings in 2004 and actually suggested that we do a conga line around the room because this is an important initiative. Currently I'm Vice President of Information Technology and Informatics at Theravance, one of approximately 900 mostly small to mediumsized biopharmaceutical companies in the San

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Francisco Bay Area.

Where it happens to be

38 degrees this morning. So just some facts. Small to

medium-sized biopharmaceutical companies like Theravance play a critical role in new drug development. And according to statistics

compiled by PhRMA and bio trade associations as much as 70 percent of new drugs in major disease categories are being developed by biotechs, and many of these, if not most of these are being developed by small to mediumsized companies. As such, any new

capabilities that allow a small biopharmaceutical company and its many partners, CROs, large biopharmaceutical companies, academic research institutes and others, to improve their ability to bring safe, effective drugs to market sooner and for less expense are a win-win-win for everyone, but especially patients. So talking with many other small biopharma and having just submitted our first NDA electronically to the FDA, I believe that

CRIX has the potential - and it really is potential - to not only streamline electronic transfer of data to the FDA, but also to improve the processes for collaboration with industry partners in the future. I think

CRIX can provide cost savings and scale efficiency if CRIX supports use and adoption of common standards for regulatory submission by all stakeholders. That's industry, Today we find a lot

government and academia.

of inconsistencies and overlap among the various standards and the interpretation and use of these standards by multiple parties. So CRIX with its vision of a shared infrastructure and tools used by all has the potential to address these issues, thereby increasing the efficiency of exchange and making interactions and decisions easier, faster and cheaper. Also, CRIX because it is standards-based can also potentially make it

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easier and more cost-effective to collaborate with our many partners. Standards by their

nature facilitate the exchange of information, that's one of the reasons you use standards, and so - but today there's a very steep learning curve and cost to adopt these standards. If the shared CRIX infrastructure can provide capabilities to create and use data in standard formats and make validation of compliance with standards easier, then CRIX will have a favorable impact on the cost and time it takes to bring new treatments to market. Finally, the CRIX community has the

potential to ensure that the standards address the needs of all stakeholders, not just big pharma. And so I think it gives a

voice for small biopharma, and I think that's going to become important in the future. One side benefit of CRIX that I don't think we even understood when we started this effort is that there are other services - once you have an electronic

infrastructure for regulatory submission and for collecting information in standards structured format, you have the potential to leverage those systems in the future. CRIX also provides potential gains in interoperability of clinical systems in the future. And so for example FIREBIRD, the So

CRIX clinical investigator registry potentially provides and authoritative source of investigator, site and protocol information for connecting patients to trials. And this is critically important as

recruitment of patients to clinical trials is a huge problem. According to market

research, upwards of 40 percent of clinical trials costs out of nearly $6 billion spent annually on clinical trials is tied directly to patient recruitment, and greater than 80 percent of clinical trials have major recruitment delays. going away. And these costs aren't

I have more detail here in my

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testimony, but I won't read it. to find a new way. line.

But we need

I think that's the bottom

We need to find a better, more cost-effective ways to do drug development. CRIX addresses one piece of the overall problem. With the CRIX Initiative we have

the potential to stay focused on the science, the medicine and most importantly the patient rather than the information technology infrastructure. And this is critical to all

of us because some day all of us, our family, our friends and our colleagues will be patients. When that happens, we will need

and want the best possible, most costeffective and safe treatment. And as my

mentor at the NCI Dr. Ken Buetow always says, the question is not why now, but why not sooner. With that I will hand over to Robert

Beck who will provide the research center perspective on CRIX. Thank you again for

allowing me the opportunity to speak. DR. BECK: Thank you, Sue. I

would also like to thank the FDA and the NIH for the opportunity to speak today. is Bob Beck. My name

I serve as the Vice President

for Information Services and the Deputy Director of the Population Sciences Division at Fox Chase Cancer Center in Philadelphia. I'm also an outside director of IDM, a development stage public biopharmaceutical company. I'm familiar with the CRIX

Initiative through activities in the strategic planning workspace of the Cancer Biomedical Informatics Grid, or CABIG. I'm

speaking as an individual although attempting to represent the academic health research community. We believe that the Clinical

Research Information Exchange offers an unparalleled opportunity to strengthen the academic clinical research community. Managing clinical research at an academic cancer center has logistical, regulatory and management challenges. At Fox

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Chase we handle over 150 active protocols from individual investigator-initiated projects to industry-sponsored trials, large NIH cooperative group trials. Each protocol

of course has its own forms, procedures, addresses, rules, regulations. Investigator-

initiated protocols are particularly difficult. Although the sine qua non of

clinical research at an NCI-designated cancer center, these are quite challenging to export beyond the single institution where they're developed due to lack of standardization across institutions or protocols. trials, while offering some limited standardization within a corporation's offerings, generate their own problems. one colleague comments, every time I work with a new sponsor it costs me money. That's As Sponsored

because new sponsors mean new forms, new organization of trial data and other inefficiencies that standardization of course could address. We recently celebrated the 20th

anniversary of Fox Chase Partners, a consortium of over 20 institutions in Pennsylvania, New Jersey and Delaware. Our

partners participate in clinical research, add many patients to clinical trials and form the substance of a community clinical oncology program, or CCOP. However, the

problems of clinical trial management are multiplied twenty-fold when extending them to this community. This group could function as

a single collective entity with improved automation and standardization of protocol management and investigator data. CRIX, in particular the FIREBIRD initiative, offers several positive features for busy academic clinical research organizations. Cost savings can be achieved

by reducing paper shipment, reconciliation and storage costs, by creating a single electronic master repository for investigator regulatory documentation for the entire

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institution and its partners, and by minimizing the number of documents the coordinator or investigator must manage. Increased standardization can arise through the establishment of a single industry portal available for use between all sponsors, all sites. This would particularly help our Standardization across

partners, our CCOP.

sponsors of technical management of regulatory documentation would be a plus as would the standardization of idiosyncratically designed forms. Establishing safe credentials that can be used for other systems would represent a further important step. Also, improved cycle

time is of import not only to industry but to busy academicians. Reuse of frequently used

information leading to reduction in the number of errors is part of FIREBIRD's appeal. Also, accelerated regulatory

document package completion will shorten the time required to initiate a new study, whether initiated by an individual

investigator, a cooperative group, or an industrial sponsor. Most attractive to us is

the reduction of redundant sponsor requests and data entry for routine contact information. We of course want to enter and

maintain our static data once for all sponsors. When changes then occur, updates

through a central portal would provide accurate information to all our sponsors simultaneously. Automation of the clinical research enterprise at the federal level allows more protocols and sponsors at the academic site without increasing staff resources. FIREBIRD and CRIX promise to

minimize paper and paper-handling costs and thus to simplify the entire compliance environment. This in turn could enhance

patient safety even as it facilitates investigator compliance with appropriate but burdensome regulation. Most exciting is the

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potential of these systems to leverage other information management and informatics investments, such as the electronic health record. Fox Chase Cancer Center as part of

its participation in CABIG is developing a clinical data warehouse that can take results of translational and clinical research directly into consensus records populated by the electronic health record. This project

can be rapidly accelerated by the sort of standardization offered and promised through CRIX. This project can be rapidly

accelerated with the sort of standardization offered through the Clinical Research Information Exchange which will leverage institutional electronic record systems and clinical research technologies for the benefit of all participants. Now I'll hand

it over to Diane Paul, a patient advocate who will provide her perspective on CRIX. Again,

thank you for the opportunity to speak today. MS. PAUL: I'd like to thank the

FDA and the NIH for the opportunity to speak

to you today.

My name is Diane Paul and I'm

a 13-year survivor of advanced ovarian cancer. While I belong to a number of

different advocacy organizations, I am speaking to you today as an individual. I am

a member of the CRIX steering committee and have been for the last year and a half. Over

the last 13 years I have witnessed firsthand the roadblocks that exist in bringing treatments to patients. Time after time I've

seen patients willing and able to enroll in clinical trials who have to go back on standard treatments because of the delay in opening of trials. I've seen patients

waiting for new drug approvals die before those drugs get to the marketplace. When

treatments do receive approval, they are often no longer of interest to patients because newer, less toxic methodologies are emerging. Prior to January of 2000 I was

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employed in the Information Technology Department at the Fashion Institute of Technology in New York City as a systems analyst. When I first came to FIT in 1979,

there were many problems with admitting and enrolling students in a timely fashion. different silos of information which the admissions, financial aid and registrar's offices maintained caused similar problems to what I see as issues in the drug development and approval process. The first step in The

solving these problems was to get representatives from each area to work together towards a common purpose. Communication between the FDA, the research community and the pharmaceutical industry is the first step in breaking down barriers which hamper them all. The CRIX Initiative

provides the framework for communication so areas of agreement can be documented and real problems can be defined and solutions explored. With this type of framework all

three entities can work together for the

public good. The CRIX Initiative will enable the standardization and electronic transfer of data. This will both speed the It

development and the approval process.

will service patients in a number of ways. Treatment choices often must be made - sorry about that - in a relative short period of time in order to best serve the patient. Patients are often unable to enroll in trials when they and their doctors deem it appropriate because of the delay in the opening of the trials. improve accrual rates. Timely openings will This will have a

ripple effect on the time it takes to complete the trial and get information about efficacy and toxicities to regulatory agencies and hopefully to increase the speed with which treatments are available for the public. Cost savings resulting from

standardization and electronic transfer of

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data should allow for more investment in new therapies as well as savings in treatment costs for the public. Better standardized

information from trials should provide more meaningful treatment information for doctors treating patients in the clinics following the completion of trials and treatment approvals. Currently cancer patients and their doctors need to search various databases in order to find trials which are open and available. One way the CRIX

Initiative should help is to establish ways for patients to find appropriate trials across both the private and the public arenas. Matching patients to trials across

the health continuum will be a big step towards improving accrual times for trials and the ability to search the public and private sector at the same time will allow better information for patients and their doctor to determine what trial choices exist and what is the best choice for the patient.

Patient advocates work on many levels of research and treatment development. The CRIX Initiative includes patient advocates in all areas of its governance structure to assure that patients' concerns will be heard and met by the initiative. volunteer my time to the CRIX steering committee because I believe it is of utmost importance that we change the current system to better service patients. I feel the CRIX I will now I

Initiative will help to do that.

hand over to Dan Ruggles of Liaison Technologies who will provide a perspective on how other industries have dealt with the establishment of exchanges. MR. RUGGLES: Thank you.

My name is Dan

Ruggles from Liaison Technologies speaking on behalf of Bob Renner, our CEO, who could not make the meeting today. I'd like to thank

the FDA for the opportunity to speak today and to share our experiences in setting up

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and operating a consortium exchange. Technologies, formerly known as

Liaison

ForestExpress, was founded in June of 200 and is headquartered in the U.S. with operations in Europe. company. We are a private for-profit We act as a shared infrastructure

provider for an exchange will I'll define later in this discussion. Liaison has been

funded by Global 1000 companies with a clear intent to foster and promote standards with our implementation of an exchange. Today we

operate a set of systems that process about 3.1 million messages per month with over 3,100 connected companies. There are two types of architectures in an exchange. They're either The

point-to-point or a hub-and-spoke.

point-to-point model involves a series of direct connections between two unique endpoints. Most industries have deployed the As

hub-and-spoke model for their exchange.

can be seen from the table, these exchanges have gained significant momentum and business

model validation over time, and involve the active participation of competitors to work together to help drive down their own respective costs and improve their cycle times. Some of the common themes of these

exchanges are it does require industry leader participation actively leading with visible high-profile companies, and it does require a clear separation between the standards bodies, generally not-for-profit, and the operating the exchange, which generally follows a profit model. Significant

investment is required if you want to start one from scratch. Nearly all successful

exchanges report investments of between $100 to $250 million, mostly in startup costs, before reaching substantial benefit for the members. Now I'd kind of like to talk about the functions. There are usually three The

functioning parts in an exchange.

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initial driving force is the top one, the industry association, which sets and promotes standards, governance and coordinates funding. They frequently act as the voice of It's a low

the industry, marketing champion.

financial investment initially, but requires a significant amount of time with senior industry leadership resources. On the lower

left to yours is the shared infrastructure operator, Liaison. We actually operate and

execute the shared platform which we helped build and design. And last there's the This is

certified solution providers.

nothing more than a typical leverage model using economics to speed the adoption of the standards and in some cases the adaptation of the standards over time based on real world experience. Our experience has shown that

validation and enforcement activities for industry standards can only be maintained through a shared services model. Without the

exchange, certified solution providers and individual companies will deviate from the

standard to accommodate their individual needs. The exchange acts as a control point Companies used

to localize those exceptions.

to the exchange can provide advantage in terms of cost economies, quicker to market and improved cycle times. I'd like to share with you some of our key learnings. From our experience and

observation of other exchanges as well as our own, getting started required strong industry leadership and commitment. requires a long-term view. This model The economic

benefits may not likely be reached for five to seven years, although a breakeven operation may come within two to three years if managed carefully. The consortium

exchange is a proven model as exemplified by my previous table. The three key

stakeholders all have to participate, which is the association, the shared infrastructure provider or the exchange operator and the

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certified solution provider.

And lastly,

it's a long-term commitment by all stakeholders for success. Now I'd like to

hand over to our last speaker, Mark Adams, from Booz Allen Hamilton, to provide a service provider's perspective on the CRIX Initiative. Again, thank you for allowing me

the time to speak. MR. ADAMS: I want to thank

everybody again for the opportunity to speak to the panel from the service provider perspective. As said, my name is Mark Adams.

I work for Booz Allen Hamilton which is a management consulting company located here in the Washington, D.C. area. I'll be

addressing these questions in my remarks today. The CRIX service delivery providers will be responsible for the construction, deployment and operation of tools and components of the CRIX service. The providers will also ensure that the development and service provisions meet the

compliance requirements that are outlined for them. The provision of these services is

provided to the community of users via a contract which will provide the platform for the service level agreements and other activities. CRIX International would select

one or more service delivery providers to deliver these services to the CRIX community and would contract with these service delivery providers providing structure, scope, governance for their activities. These service delivery providers must be independent from CRIX International and can either be for-profit or not-for-profit organizations. One of the key recommendations from industry is to select a single prime contractor to act as a service delivery provider. This service delivery provider

would then subcontract with the entities providing the specific subcomponents to

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comprise the CRIX services.

The service

delivery provider subcontracts with specialty vendors, then provide the key project activities. Thus each subcomponent can be

supplied by best-of-breed groups without burdening the CRIX community with the need to identify and contract individually with all of them. This includes software development,

deployment, hosting, support services and others. Industry regards a prime contractor as the most efficient way to provide the CRIX collection of service modules. This also ensures that the

interactions between those providing the specific services to the community are consistent and flexible, and also allows new services and/or service providers to be added to the process without disrupting or adding complexity to the users of the CRIX services. Additionally, consistency and synergy can be realized by providing shared help desk, software support and other shared services

for all of the tools and capabilities that are provided to the CRIX community. In this

simplified contracting and funding approach, all the users of the CRIX services would execute a single contract with the prime contractor for each of the desired modules which additionally provides for a single channel for the collection of service fees. A single point of contact also provides a mechanism for single, well-defined issue escalation and dispute resolution mechanisms and provides for flexibility in resolving such issues quickly and effectively. The funding model for CRIX International would depend on a set of initial contributions from industry founders. These contributions would provide the foundation on which the initial organization would be formed and then service fees for usage would provide an ongoing revenue stream to support module operation support and

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maintenance activities.

These service fees

would go to CRIX International and would be based on the levels of usage and an organization's ability to pay. A CRIX user's

ability to pay would be measured by the firm's global annual sales where firms with higher sales are expected to pay more for services. The annual fees for founders and

non-founders would be set in relation to the projected market share in order to minimize the capital investment requirements and achieve a self-sustaining cash flow by the third full year of operations. This will

ensure that the services provided by CRIX International are available to all organizations regardless of their size and stature. As the CRIX organization reaches a

self-sustaining level, the fees can be reduced or excess funds may be directed towards the development of new services. The

process of selecting commercial suppliers for the prime contractor and for the subcontractors would be done via standard

competitive award process which will ensure a fair, open and objective review and selection of vendors in all the roles. This ensures

maximum fairness in the process and the best value to the users of CRIX services. Through the proposed process the community involved in all the process and phases of the new module development, both that carried out internally and externally to the CRIX International. From a governance

perspective, once the prime contractor is in place, industry recommends establishing an advisory board to ensure that the explicit implementation meets the needs of the customers as well as CRIX International. This would provide management oversight and leadership connecting the community with CRIX activities. To facilitate this, it is

proposed that the CRIX International will oversee the selection of modules, the service modules, in an inclusive manner that ensures

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that appropriate business analysis, incubation and development take place. This

provides a mechanism for successful, costeffective development and deployment that meets the customer's needs and adheres to regulatory requirements. So in summary, the proposed structure yields several advantages. Third

party oversight ensures vendor neutrality and cost efficiency. Secondly, single service

delivery provider reduces the contractual complexities and it mitigates the risks associated with coordinating multiple vendors. Thirdly, the approach promotes an

open dialogue and involvement that is inclusive of the CRIX community stakeholders in ensuring that all interests are met. Finally, the investment review, incubation and development oversight ensures service module selection is technically and fiscally sound. Thank you for allowing me the opportunity to speak to you today. My

colleagues and I would be pleased to field any questions the panel may have. ask Deb up. Thank you. MS. BREMER: I thank you all and I Dr. And I'll

will open it to the panel for questions. Mittleman? DR. MITTLEMAN:

I'd like you to

speak a little bit to how you see the role of government in this. I mean, I think there

are a lot of enormous strengths that can be brought by having a lot of aspects of the private sector be involved. And how the

research community and the FDA interface really will work here and how they can both provide scientific input, expressions of needs and opportunities with the private sector folks is a little less clear to me given the governance structure you're describing. MS. BREMER: Sure. Well first of

all, I think the first thing we want to say

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is we think it's absolutely necessary that the government agencies - thank you, Diana. I appreciate that. My tall friend. But that

government agencies, particularly the FDA, are a part of this and so I would say there are a couple of different ways. One is

formal participation in the governance structure. The bylaws do call for a board of

directors that has I believe up to four seats available for government agencies. And

again, we would foresee that certainly one of those could be the FDA, perhaps NCI as well and others. Secondly, we would also be

looking for active participation in the exchange service itself. And I think most

people feel, you know, in terms of lessons learned and things like that, if that is not a part of the model going forward we would be less than successful. And I think that

active participation starts very soon building on the foundation of the memorandum of understanding between FDA and NCI with FIREBIRD in particular. And we hope that we

could kind of exploit that, expand that and make FIREBIRD available for commercial usage as well. MS. PAUL: I also think it's

critical to the public that we have governmental involvement in this project, I think particularly since it's going to probably involve sensitive data. Having the

government watchdogs on the various committees is I think important. It will

make the project much more palatable to the public. DR. MITTLEMAN: To extend that

just a little bit, have you also thought about other governmental agencies, EMEA, et cetera, and how you want to interface with them? MS. BREMER: Yes, we have. So as

it's called CRIX International, the emphasis is to be able to ultimately operate in a global environment. And I think it was Mark

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that talked to the concept of advisory councils and advisory boards. And our

thoughts are that essentially we would have regional - over time we'd have regional advisory councils so they're, you know, the first would be what we have here in the U.S. and then as that broadens we would foresee, for example, the European arena having an advisory council. Those advisory councils

also have board representation, one from each council. DR. WOODCOCK: DR. LUTTER: Dr. Lutter. Earlier speakers used

the words "mandate" and "incentives" and I haven't heard either word used in response to the question what role for government. maybe I could ask you are you opposed to mandates or incentives, or is there some role for such actions by FDA or other federal entities? MS. BREMER: I think mandates will So

be on a case-by-case basis depending on the service that we're talking about. There will

be some services that in order for them to be successful I think it'll you know, it'll become intuitively obvious that it would have to be a mandate in order for it to achieve its outcomes. Others will you know not have In terms of

those same characteristics.

incentives, I think the incentives are essentially the benefits that we've talked about that are to be gained from something like this. For example, lowering the

development cost for you for independent entities, or lowering the development - the review costs from a regulatory agency kind of perspective. So besides the incentives in

terms of speeding drugs to patients which is something that has you know in our hearts also feels good, there are the financial incentives to the folks that are involved. DR. WOODCOCK: Ken Buetow. DR. BUETOW: I assume it's safe to Other questions.

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assume you guys are interested in third party solutions? You wouldn't be opposed to that? MS. BREMER: assume that. DR. BUETOW: I'm intrigued what I think you could

you all see as the relationship of an entity such as this to the existing standards development organizations and how this group could, would play in the further generation and propagation of those standards. MS. BREMER: comfortable. DR. BECK: I see us as an umbrella Bob, if you're

organization that serves as a very large tent under which companies, academic institutions, the public and government can essentially coalesce. And so standards bodies, the

governance structure will be reviewing their work and basically we will provide a stimulus I think to standards development. I can't

see any other role for an organization like this to be other than a stimulant, not an and maybe, you know, reciprocal participant

on some bodies, but not actually doing the standards development themselves. MS. DUBMAN: Just to echo that, I

think you know we're going to try to leverage whatever is out there and not reinvent the wheel. And so we are using for example CABIG

guidelines in developing solutions so that they're interoperable. And you know, I think

we're working you know closely with CDISC and ICH and other organizations to make sure that we're not, you know, again reinventing the wheel. MR. RUGGLES: One additional quick

comment and that's, you know, when we're talking about some of these additional seats, I think it's envisioned that standards organizations like CDISC and others would have opportunities to actually be on the governance board of the organization. So to

make concrete some of these recommendations they'd participate.

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DR. WOODCOCK: more? No. Okay, Armando? DR. OLIVA:

Ken, do you have

I recognize that CRIX

International just came into being this month, so maybe this is an unfair question. But there are many stakeholders that obviously would like to see CRIX succeed and to borrow a phrase from someone else on the panel, why not sooner. this. And my question is If a

My real question is this.

stakeholder sees the need and maybe even has the resources to develop a service, a shared service, what's your advice on how that stakeholder should proceed at this point? MS. BREMER: So first of all we

welcome stakeholders that see a need and are willing to get something started, to incubate it so to speak, and FIREBIRD is an excellent example of essentially that kind of a concept. So we don't discourage it.

Certainly though it would be very helpful the more stakeholders at large have an interest in something, the better the model is going

to be in terms of usage.

So if there was,

you know, a single stakeholder that wanted something, but there wasn't broad interest in it, it may not be a viable long-term model. So there's a variety of different things that we'd use to determine the order of services to be brought into the CRIX environment. certainly the broad stakeholder community represented in a large way through the advisory councils, in a very focused way through the advisory councils and through other input will help advise the board of directors in terms of what are the prioritizations so to speak of the next services to be provided. we don't discourage that. DR. OLIVA: But we certainly We welcome that. And

So is there a process

or is there a mechanism right now where new services can be proposed or discussed and entertained for prioritization? MS. BREMER: Back to your point of

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just being formed formally as of about 11 days ago. I would be remiss if I said that To date what we

there was an active process.

have are the startings of the board of directors with the founding members and our next task is to round out the board of directors, get some officers in place and then start working on service providers. in parallel to that we will obviously be working on processes. As soon as we get a But

few more people onboard that is certainly part of our plans. MS. DUBMAN: At the last CRIX

meeting we actually did discuss an additional new service to bring forward for CRIX and actually the discussion actually ended up talking about what is the process. I think

we will get those processes in place quickly now. DR. WOODCOCK: DR. BUETOW: Dr. Buetow. So to complement the

question on services, there's obviously the interest in the prioritization of what

services come onboard, but what about - I think from previous speakers there was discussion about also, concern about access to services and what would be in place to guarantee that - especially it sounds like as this is proposed there might be - "monopoly" is the wrong word, but perhaps singular source of services. How would you guarantee

that services could be provided to all of the stakeholders in a timely fashion and that it's not a few 800-pound gorillas that consume all of the resources and then smaller players are actually left on the sidelines? MS. BREMER: So first of all I

would say again, substantial emphasis will be placed on what the advisory council and the CRIX community at large recommends. repeat enough, and I do represent individually one of those big 800-pound gorillas, but I can't emphasize enough that we do not see ourselves being successful in I can't

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this not-for-profit kind of entity, in this overall shared infrastructure approach, unless there's active participation by all stakeholders. So it is not in the big

gorilla's best interest if we do things that preclude folks, you know, that aren't those big gorillas from participating. MS. MCKENZIE: And I'd also like

to add that as we think about the overarching governance body, our expectation is that we have government representatives on that body I think first and foremost. And I also think

that in forming CRIX International our goal is to make sure that there's an oversight body that's looking out for the interests of the community. And one of the expectations

that's either outlined in one of the slides or in the executive summary is that we expect to put pricing in place that is actually tiered based on the size of the different organizations that would want to take advantage of the services. MS. PAUL: And the governance

structure includes patient advocates at every level including on the advisory board. And I

and most of the people I know who are patient advocates take that very seriously and I think Ken you know we will be there watching, so. DR. WOODCOCK: from the panel? Other questions

Dr. Lutter. The services that you

DR. LUTTER:

offer would presumably be for sale at cost because you're a not-for-profit. Would they

be available to any interested party, or only people who are in some sense members or subscribers to CRIX? MS. BREMER: We see the services

as being offered to, as the bylaws point out, all members of the CRIX community. And there

are different kinds of members of the CRIX community, from founding members as we talked about, you know, are onboard today, to associate members. And the associate members

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are essentially the users of the service. there is a formality to saying, not a bureaucratic formality, but there is an

So

active choice of being a part of the service and paying fees, again, commensurate with ability to pay so to speak. know, an active choice. So there is, you

I'm not sure if I've

exactly answered your question, Randy. DR. LUTTER: For the non-associate

members, they would have no access without becoming associate members? MS. BREMER: DR. WOODCOCK: DR. BUETOW: mitigation, I'm curious. That's correct. Dr. Buetow. In terms of risk This is, again, a What

relatively large centralized activity.

are the strategies that actually mitigate risk with respect to the availability of these services if you all decide at some point in time that you don't like this? What's the role of open source? What's the

role of open standards and other components in what you all would develop? Would these

services, infrastructure and other components be able to be run by other people besides this so-designated entity? MS. BREMER: Certainly. If you

think about the prospect of we are looking for initially a core service provider, again, we would be giving that service provider oversight in terms of the order of priorities of services and things along those lines, but they would be essentially running the day-today operations, providing the user support, et cetera. So if the, you know, although we

don't anticipate - we anticipate this being, that we're all in for the long haul, but if that should happen, the core service provider, if the company chose to do so, could potentially keep things going. DR. BUETOW: So would the services Would

definition be in the public domain? there be a plan to share the services

definition as part of this public domain?

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MS. BREMER: DR. WOODCOCK:

Absolutely.

Yes.

I have a question.

I found the presentation from Liaison Technologies very interesting. My question

is this set of services involves to me something beyond what you presented as types of services that were mainly for industrial partners. It involves health, it involves

patients, it involves healthcare providers and so forth. dimensions. It seems to add some extra Have you seen any models where

there are many stakeholders with major stake beyond the industrial partners in the exchange? Maybe the financial networks, for

example, where they're all moving their money around? MS. BREMER: come to the microphone? MR. RUGGLES: Yes, the financial Dan, do you want to

industry, VISA is an excellent example on the security side of it, and that's probably one of the better examples out there. We do buy

and sell and keep track of things in that

regard, and in terms of confidentiality, in some cases that information has to be encrypted. So there is some similarity, but

nowhere near some of the things that you've talked about or discussed here today. DR. WOODCOCK: Complexity. It

strikes me those financial networks for example, there are users such as me. I mean,

I'm just, I'm not really a user because I'm always using some industrial partner's whatever, setup, but is that how it would be envisioned here, that a lot of healthcare types and the patients and so forth wouldn't have to be members of the CRIX community, they would simply be users of this network on behalf of the entities that set it up? MR. ADAMS: So we create, as an

example, we create services as a solution. And one of those services could be very much the way you do your banking, as an example. So I'm trying to use it as an illustration as

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opposed to I don't want to design or architect anything. But yes, it could be a

web-based sort of service that's going back to the pharmaceuticals also feed information to security. Kind of keeps things separated

as to what you can look at and what you can do. DR. WOODCOCK: there any other questions? DR. OLIVA: Thank you. Armando. Are

Yes, I'd like to probe

a little bit this whole idea about competition. Using the VISA example. As a

user of VISA, I can shop around for the best rate or the lowest annual fee or the perks. And how would that - how do you see that level of competition? using the CRIX model? MR. RUGGLES: I think the key way How would that work in

in which that would work, and one of the reasons that the organization was sort of designed with this multiple tier aspect to it is such that the stakeholder is participating in it, and that includes the government

representatives.

The representatives broadly

of the individual stakeholders then initiate a competitive and an ongoing competitive process at two layers. One for the general

overall service provider who's going to act as sort of the prime contractor, but also through that to the folks providing services up through that process. So there's two

layers essentially of traditional competition going on to ensure that both the quality of the service meets the requirements of those stakeholders. Maybe unlike many companies,

the stakeholders themselves are those to whom the organization is beholden, not you know shareholders out in the world. But those

stakeholders then initiate that competition that can be ongoing. So essentially you're

getting competition for the services that are then provided more or less through the central mechanism. So it's not quite the

same where you could go to any of several

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shareholders any time, but there's competition for those roles and that's ongoing and controlled by those who are using the services. DR. BECK: along that line. Two other thoughts

First, FIREBIRD itself is So there's nothing

an open source solution.

that would preclude somebody out there in the community, in the wider community, in the non-CRIX community from creating or modifying or improving FIREBIRD and providing that as an alternative to this entire enterprise. Secondly, there's nothing in this enterprise that would preclude the agreement to host more than one service provider for a particular service just like VISA versus MasterCard at the level below - at the operating level. So there's no reason why,

especially if we focus on some of the things we've learned through CABIG and other initiatives, a bias toward developing prototypes in open source and then taking them to the point where they're ready to be

supported or taken out.

There's no reason

why there couldn't be more than one solution at any level. DR. WOODCOCK: We'll have to - go

ahead, and then we'll have to wrap this up. MS. MCKENZIE: point. Just one more

I think one of the things that's made

the financial services model so successful is the adherence to standards. And I think in

this case competition becomes better the more they adhere to standards. It makes it easier

for them to come and fit into the service so actually it creates just a nice momentum that we're looking for in our industry for adoption. DR. WOODCOCK: All right. We

thank the entire CRIX community as represented here for your presentations. next two speakers are Ed Tripp, Program Director for eSubmissions at Abbott Laboratories and Bill Rosen, Executive Our

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Director, e-Health Policy and Standards, Pfizer Global R&D. MR. TRIPP: I feel a little bit

like following a production of A Chorus Line. Dr. Woodcock, distinguished panelists, ladies and gentlemen, my colleague Bill Rosen and I would like to thank you for the opportunity to present on behalf of the Pharmaceutical Research and Manufacturers of America on the subject of electronic submissions and publicprivate partnerships. electronic submissions. First I will address Then I'll turn the

podium over to my colleague Bill and he will speak and address public-private partnerships. The member companies of PhRMA

spent nearly $40 billion on pharmaceutical research last year and with such a massive investment we have been long been advocates of data and information automation that can lead to improvements in healthcare through better access to information, and that in itself could lead to better decision-making. We wanted to make our position

clear.

We fully endorse a plan to move to an

all-electronic submissions environment and to that end we've partnered with FDA to establish electronic capability for individual case safety reporting, structured product labeling, annotated ECGs and other standard data and exchange formats. Our

reach goes to working with ICH, CDISC and HL7. We've got broad leadership involvement

with the ECTD working group, the SPL working group and today with the regulated product submission, both the leadership and testing teams. And our organization, the members are

implementers and we want to both identify our concerns and add our voice as proponents of the public-private partnership concept. So as we look at some of our top goals on electronic submissions, the first goal deals with developing end-to-end electronic environments. And when we talk

about end-to-end, we're talking about dealing

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with process and information flow upstream and downstream of submissions. I want to

emphasize that a common environment facilitates information sharing and transfer of information all the way from discovery to product retirement. So its scope needs to

encompass all transactions throughout the product lifecycle. As Dr. Edwards pointed

out, we need to be looking at advertising information as well as submission data. It

needs to be the entire scope of the process. Goal number two goes to harmonized processes and data that increase data access and dissemination, and that leads to better analysis. Critical to the success, we

believe having a long-term plan with sufficient detail in the first 18 - 24 months and establish long-range goals running out over a rolling five years will help facilitate the right activities and speed adoption. The plan or roadmap needs to lay

out the key milestones for each initiative that will in the end lead to an end-to-end

electronic system. The most effective standards are broadly harmonized. We were just talking Imagine what

about electronic banking.

electronic banking would be like if national boundaries and regional jurisdictions dictated that they use different standards. We would never move money out of this country and yet that's exactly what we're doing in the healthcare industry. So, how would we benefit by an electronic submissions environment? That

question depends on how it's implemented and it assumes the assumption of effective standards. And by "effective standards" we

mean that they're harmonized and well established or stable. And the focus then

can be directed at the science and at information access and retrieval, and that information access and retrieval will exceed our best expectations. We only have to look

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to the Worldwide Web to see how standardization of data and information can increase our access and our ability to react. Harmonized standards promote consistent processes and procedures, reduce redundancy. Standardization of clinical and

safety information and its transmission in a globally harmonized format lays the foundation for a future vision of a global electronic health record. And from my

perspective that needs to be the target in that arena as well, not a U.S. electronic health record, but a global electronic health record. I do not want to go to Germany and

find that my health record doesn't do me any good there. Now the use of electronic submissions requires standards, but for standards to be truly effective they must be harmonized to achieve interoperability. If

we drive to globally harmonize standards, we enable the use of the information not only for marketing reviews, but for many purposes

across the healthcare domain.

And working to

develop standards and processes for an endto-end electronic environment should be viewed broader than an FDA objective. All

stakeholders need to be engaged to maximize the use of the data and the information for improvement of patient healthcare. To the question of wouldn't allelectronic submission environment change your ability to initiate in a timely manner the studies supporting your regulatory submission. Well, from our perspective the Can

question needs to be re-worded slightly.

a sponsor improve the conduct and analysis of a clinical trial with an all-electronic submissions environment? undoubtedly yes, but. correctly. And the answer is

It needs to be done

Imposing standards on legacy

processes designed to utilize paper will not speed up study startup. We need to evaluate

and redesign the process as well as develop

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the standard to achieve a more efficient overall process. We need to extensively

pilot the standard and the processes and allow sufficient time for tools to be developed and to mature. However, the impact

of an improved harmonized electronic standard that supports more efficient business processes for data collection, monitoring, review and analysis will likely offer more dramatic gains and speed and cost reductions for both the industry and the agency. If you

think about it, you wouldn't look at an old process that required triplicate NCR paper and we all remember that I think. Most

everybody in the room remembers that - and automate it by having your printer automatically spit out three copies. engineered the process. We re-

We shouldn't combine

our efforts to the development of data standards and automating the paper processes. We need to leverage the automation by redefining those processes. Not having a clearly stated

compelling business case for electronic submissions or any of the components of electronic submissions hinders adoption. And

this - we've gone through the discussion of mandate, no mandate, incentives. The bottom

line is there needs for each component of an electronic submission system there needs to be a clearly stated business case. That may

be the gun's at your head, this is a mandate. It may be that there's an incentive. It may

be here's a rationale and a way to look at it, and you're going to save hundreds of thousands of dollars if you adopt this. But

it needs to be clear and stated up front or we get this fuzzy participation. There's

some companies that want to be on the leading edge. There's some companies that want to be

on the trailing edge. The benefits can be realized with the comprehensive long-range plan where every one of those initiatives has a compelling

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business case and folks can see where the end game is and plan where along the path that they want to join in the process. Standards

churn, or the movement from version to version, increases cost of implementation and results in continual reinvestment. And we

have many players who sit on the sideline waiting for the dust to settle before they jump on. You only have to look at the We

history on SPL to know that's the case.

still have some folks sitting on the sideline waiting through their first submission on SPL because that standard has churned and turned over a number of times. A major impediment is a mixed environment with too many options. Andrew

Tanenbaum, who's a Professor of Computer Science in Amsterdam and the father of structured programming, said the nice thing about standards is that there's so many to choose from. Well, we don't think that's a

very nice thing when it comes to trying to move to a new environment and we believe that

the notice to withdraw the ENDA guidance is a positive step. Are there enough entities to support the effort? question of churn. It really goes back to a Lack of a long-term

roadmap leads to confusion and that combined with instability of standards delays vendors from entering the market and causes industry to take a wait-and-see attitude. So if

there's a lack of testing before introducing a standard that can erode its value. And

although the time to develop a well-tested stable standard is longer, the overall cost to implement ends up being much less. Faster

is not always better and through piloting standards before implementation we can obtain stable services and tools and actually get faster adoption and lower cost. Additional costs associated with implementing a particular format of standard. Best guess is the move from ENDA to ECTD is

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or will be more costly than the move from ECTD to RPS, but that in part depends on how good a job we do testing and developing the RPS standard and the processes around it. There are also hidden costs dealing with behavioral change and that happens both at the agency and the sponsor. We still get

requests from reviewers to provide paper. That sends kind of a funny message when we're trying to move our organizations along to an e-environment. And our scientists are

reluctant to move from a paper environment because they have to learn to evaluate not just the content, but the bookmarking of documents, the hyperlinking of documents. The analogy is everybody in this room can pull out their PC and type up a several-page report and print it out. turn it into a webpage? How many of you can And that's what we

ask folks to do when we create an electronic submission. So there are costs associated There is a

with finding the right resources. shift of skill set.

There are costs in

modifying document management systems to accommodate changes in structure and meta data every time we shift a standard. And

then there's costs of new publishing tools because not all - we can't count on the tools that we have for one standard being developed and made available in the right timeframe for a new standard. Are there parts more costly to convert? And the answer is yes. I think we

heard this also from some other speakers earlier today. Any change in electronic

format that ripples downstream into our internal data collection processes actually has an enormous cost associated with that change. There are, at least for mid-sized to

large companies, there's a substantial investment in data collection systems, and when the format changes, there's a large reinvestment to change those systems. Sometimes we get lucky and it happens to hit

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at a time where we're looking to upgrade those systems anyway and other times it's totally unexpected. Once again, a well-laid

out 5-year plan will help us better stage that kind of investment, but it is possible for the fully implemented change to be more efficient than the previous environment. And

that requires all parties to be involved in the redesign. How much time? a number. The answer is not

You've got to have the right

processes in place regardless of the time it takes. We learned a number of lessons

implementing SPL and one of them was that the lack of scenario-based development and testing led to frequent changes and additional complexity. You need to crawl

before you walk and walk before you run and that means engaging all the stakeholders in developing the new process, then develop the standard, do scenario-based testing, pilot it, be comfortable with the results of the pilot and finally document the implementation

requirements well, then take it into production. And if we do that, the uptake

will be faster and a lot less problematic. Problems arise when we skip these steps to compress our timeframes or when legacy methods for exchange aren't withdrawn. want to thank the panel again for the opportunity to address them, and now I'll turn the podium over to Bill Rosen. MR. ROSEN: thank the panel. here. I too would like to And I

I'm vertically challenged

I too would like to thank the panel

for giving us the opportunity to speak today. I'd also like to thank the multitude of you who bothered to get up this morning and get down and get into line as early as 7 o'clock, and I hope that the turnout will show the FDA and the NIH the interest that the topics that we're talking about today have for the user community. I'd also like to encourage that

community to please get your comments in by

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the deadline and judging by the number of you that are out there this morning, I hope that there will be plenty of them. Now, last night on the way down here, I don't have a slide for this one folks, but on the way down here I happened to start thinking about the history of esubmissions and some of the beginnings of the public-private partnership. Now, the good The

news is that I can remember it at all. bad news is that I do remember it.

Going

back to 1984 Research Data Corporation and Abbott collaborated to submit the first CANDA, or Computer-Assisted New Drug Application to the FDA on a VAC server, if any of you can remember what a VAC server is, that was not located on FDA property but rather was located at RDC. Unknowingly, they

delivered the first electronic submission via a trusted third party entity. the late `80s NDAs were delivered electronically at the FDA via something called ONDAs, or optical NDAs that consisted During

of scanned documents that were not easily searchable as you can imagine, but they were in electronic format. In the early to mid-

`90s CANDAs multiplied proliferously but without standardization within our crosssponsors, the scope, features, hardware, software, they all varied wildly. paid for one-off development. Sponsors

Agency

reviewers had to learn a new system each time a new application was submitted. process was not efficient. The entire

There was a sense

of frustration on the part of both sponsors and the agency due to the lack of standards. However, there was agreement that electronic submissions could increase access to information, speed access to information. These early CANDAs could not be leveraged, however, on an international basis. In 1992, the initial FDA CANDA guidance manual was published. During 1994 -

1995 the Submission Management and Review

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Tracking or SMART project was established by the FDA. The goal was to provide standards

and a system for industry to submit text, data and image files in electronic format. In the mid-`90s Document had emerged as the de facto document management standard while Adobe PDF emerged as the de facto output standard and SAS transport format became the de facto format for submitting data electronically. In 1997 the Aris pilot for

e-safety reporting was initiated and the FDA also drafted a guidance for e-submissions. In 1998 ICH, the International Conference on Harmonization, began to focus on a means to create and transport an e-submission that met the definitions of the common technical document. In 1999 the e-submissions guidance for CDER was approved in January and for CBER in November. And by 2000 a brokerage site

was presented at the DIA annual meeting and PhRMA began discussions to consider something referred to as InfoBroker which was intended

to establish a shared environment via a trusted third party. In 2001 FDA speakers

mentioned the innovative use of third party repository at the DIA annual meeting and PhRMA developed a white paper titled Issues in Developing and Implementing an InfoBroker for the Biopharmaceutical Industry and Regulatory Authorities. Also in 2001 of note

over 70 percent of the NDAs included at least some electronic component. In the spring of 2001 the ECTD or electronic common technical document specification was published, establishing the format for a globally harmonized esubmission, quote unquote, or the uncommon technical document. By 2002 PhRMA began an

effort to build the concept then known as SEBIX, the Secure Electronic Biopharmaceutical Information Exchange that was mentioned earlier by my colleague Deb Bremer. In 2004 all knowledge harvested as a

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result of SEBIX was transferred to the National Cancer Institute for further development of the concept and we thank you. You will notice during this brief history I have used the words "brokered site" "Info Broker" "shared infrastructure" "shared environment" and "SEBIX" anonymouslysynonymously for public-private partnership. Now so that I don't step on my

tongue throughout the remainder of this presentation I'm going to refer to "publicprivate partnership" simply as P3. you. In today's standards environment, it is important the terminology is standardized as well as data content and data exchange standards. We recognize that there Thank

are many definitions for the meaning of "public-private partnership" or P3. Minimally, PhRMA believes public-private partnership is defined as a secure sustainable shared infrastructure that will provide services across the biopharmaceutical

and healthcare communities.

For any public-

private partnership or P3, security and protection of intellectual property is of vital importance. As a result, efforts must

be taken to secure the infrastructure and ongoing testing is necessary to assure the effectiveness of that security. Independent

audits should be considered for this purpose. Regarding general viewpoints on a third party entity or entities providing services, PhRMA supports the creation of a P3 to provide a shared infrastructure for information exchange. PhRMA also recognizes

that the FDA has jurisdiction over other products such as devices, foods and animal health products. We believe this common

shared infrastructure should also be scalable to provide services to these other industries as well, achieving economies of scale. At a

high level the P3 must implement a common standards-based electronic infrastructure not

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only for regulatory data and document submissions but also for information review and analysis. To minimize any preferential treatment we prefer that oversight of the P3 infrastructure be a not-for-profit organization. The not-for-profit

organization should be empowered to establish contracts with for-profit companies to provide appropriate infrastructure and related services. The body that oversees the

P3 would then have the authority to establish multiple applications running on top of the infrastructure in a profit or not-for-profit manner. PhRMA advocates for a pragmatic approach where P3 has grown organically, adding new services at a speed that P3 can manage. Logistically, backup and recovery

are essential as is maintenance for both the software and hardware. service. Some random thoughts about P3 must assure 24x7

benefits.

P3 has potential to speed safe The focus

effective medicines to patients.

of pharmaceutical research should be on health sciences, not on managing and maintaining technology infrastructure that supports delivery of electronic information. P3 in this respect is an enabler. A shared

electronic information management platform therefore targets redundancies across our industry by providing a single infrastructure. We believe the business case for each new application differs across industry, health authorities and other potential users. This has to be noted as new applications and new ideas come up underneath the common infrastructure. We recognize, however, that

for the P3 to be effective it must be affordable for all, allowing for broad participation. PhRMA envisions the P3 can

level the playing field for small to medium-

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sized companies, giving them access to stateof-the-art technology at reasonable costs. This will eliminate barriers to process innovation and speed adoption of standards. The spectrum of participation includes not only large and small pharma companies, but also CROs, healthcare providers, as well as others in other regulated industries. P3 will also

facilitate two-way communication between sponsors, their business partners and health authorities. It also facilitates a truly

paperless submission. It's all about information and the shared environment can serve as a single point of reference for participants, permitting sponsors and health authorities to see the same information the same way using common tools. I must re-emphasize the need

for security, security of both the intellectual property that might reside on a shared infrastructure and security that guarantees that patient-related information

is managed appropriately. Personal health records, electronic health records and electronic data captured for clinical research purposes can be integrated at a high level, providing the right information at the right time in the right format in the most efficient way possible to benefit all parties involved, providing the standards are there to be used. Proliferating multiple P3s will not allow for efficient cross-referencing across submissions, nor will it allow for efficient information lifecycle management. The

implementation of standards must be focused on the information itself rather than an electronic information exchange platform. However, interoperability of standards that enable information exchange once again I must state is imperative. Some potential barriers. For P3

to be successful there has to be broad

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participation.

I mentioned this once before.

Several other people have mentioned it as well. Further, we recognize the potential of

a P3 across not only the pharmaceutical industry but across the broader healthcare community. If P3 is overly conservative as

it develops, the scope may be restrictive, resulting in an effort that will have a limited lifespan. Conversely, if the P3 is

overly aggressive it may spin out of control with minimal success, also with a limited lifespan. We have a need for a long-term electronic archive. Some products are on the I believe this was

market a long, long time.

mentioned by Dr. Edwards earlier this morning. If we take for instance the case of

Dilantin which was first approved in 1938 and it is still being marketed today, imagine if that was approved today and was still being marketed 70 - 80 years from now. Are we

going to be able to dig up the electronic records for that and possibly is this a

service that the P3 can play for us, as a long-term electronic archive? Other potential barriers include a lack of clarity as to the FDA's willingness or ability to participate in a P3 and this may delay or discourage full participation. This has also been mentioned earlier. Others

may simply choose to follow rather than lead, staying on the sidelines waiting for FDA and others to engage. Some conclusions. Efficiencies

cannot come at the expense of increased complexity and costs on the side of the pharmaceutical industry. We should all be

looking for win-win scenarios where information can be presented and preserved in the most effective and most efficient and cost-effective manner possible. The agency

shares the responsibility for processes they impose on the industry they regulate and how those processes contribute to the overall

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cost of medicine.

We should all endeavor for

an optimized process that creates, develops and implements globally harmonized standards that increase the likelihood of success for shared information exchange. For the

pharmaceutical and healthcare industries, we must establish a long-range plan for managing data, thereby creating a true information lifecycle. Long-range, the P3 should be

inclusive of information generated from discovery through product retirement with integration of submissions across the drug development continuum. PhRMA recognizes the

value proposition of P3 and that it varies from one region to another, but extra efforts should be made to establish globally harmonized standards. Standards in the use

of public-private partnerships can speed safe and effective new therapies to patients everywhere. Once again I would like to express my gratitude to the NIH and the FDA for allowing us to have time today to express our

opinions.

I would also look forward to

working with the FDA and the NIH and the research community on electronic submission standards and any P3 effort. DR. WOODCOCK: much. panel. Thanks.

Thank you very

We'll have questions now from the Dr. Mittleman. DR. MITTLEMAN: I was wondering

what PhRMA's view on the presentation that was made by CRIX and particularly the CRIX International kind of model, how does PhRMA react to that? MR. ROSEN: I may not be the right I've been I was a

one to answer the question.

involved in this concept since 2001.

member of the group that worked on SEBIX and I was one of the people who went over to the NIH to do a data dump back in 2004. PhRMA

supports the concept of CRIX although I would also have to be negligent if I didn't say that that is not universal across the 40-some

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odd companies that are members at PhRMA. Anything to add, Ed? MR. TRIPP: No. Dr. Levin?

DR. WOODCOCK: DR. LEVIN:

Ed, so it sounds like

there is a business case for electronic submissions. MR. TRIPP: believe there is. I believe there is. I

I don't believe we've

clearly stated it or sold it well. DR. LEVIN: But inside your

company there's a - you have a business case for? MR. TRIPP: Inside our company

we're reacting to the reactions of the FDA and say if we don't do something, we're going to have a problem. So it's more of a gun to

the head than a clearly stated business case. DR. LEVIN: So in your company

that you're not developing your own business case as far as this is going to be a benefit for us internally to our company and waiting for?

MR. TRIPP:

No.

In most cases it

is reactionary because the dollars need to compete with other initiatives across the company. And there isn't a clearly stated

and obvious business case that you can pull forward. And so it tends to be sold -

investment tends to be sold as a matter of is it a regulatory compliance issue. And if you

look at - we ran some numbers across the top 20 pharmas. If you look across the top 20

pharmas, over about the last eight years they've invested a half a billion dollars in building submissions systems and document management systems that support that and continue to invest. It's been a moving

target and it's getting harder and harder to go make the ask. DR. LEVIN: So that, so different

companies will be at different stages as far as their business cases because some have made a business case already that they want

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to go into the electronic without the FDA mandating something. MR. ROSEN: I think that's

correct. Indeed, if we take a look at how processes are changed backward of the submission process there are clearly cases where document management for quite a long time has been employed and the whole concept of submission-ready now being carried forward to the concept of archive-ready and the business case that enables the management of electronic information and also for knowledge management as well. DR. LEVIN: So it's - and this

goes back to questions that were asked previously about what can the FDA do to move forward. And it sounds like for some it's

the mandate will be the piece, but why don't you address that? MR. TRIPP: I think if we work

together on a collective long-range plan, if there's a target out there of when we collectively believe we should make the move

on any of the initiatives, then I think we ought to also have candid discussions in part around what is the business case and what's the business case for Pfizer is not necessarily the business case for Abbott Laboratory. Everybody runs their business a But you can put together

little differently.

templates that state this is how it's being used. Plug your own numbers in or plug your

own processes in and I think we've failed to do that effectively in the past. And I think

in order to make things move faster it will be helpful to do that. DR. LEVIN: who? MR. TRIPP: We collectively. And when you say "we"

There's a group of us standing up here that have been involved in this for awhile. drive standards, help, you know, drive electronic submissions and so forth and are out in the forefront beating the drum, but we Help

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need a little banner to go along with the drum, and that's the business case. DR. LEVIN: And I just, and I

question about when you're talking about staging the investment. So let's say you

decide there's a business case for whatever reason. What's that process like and how

long does that take to move your investment forward? MR. TRIPP: Well, and again it's

probably different for every company, but for us if we make a change to - if we decide to make a change to our document management system for example, not changing it but modifying it, assuming it's not a real small patch or fixed to a bug, but it's reacting to a change in the standard, we start planning for the investment in May of the year before we start making it. So the May before the

January we want to start making the advance we start planning, building up the numbers we'd start in January, and generally by the time you implement it and validate it, you're

talking September or later. MR. ROSEN: Just one comment.

Randy, I think the timeframe differs drastically with the size of organizations. Smaller companies are apt to be able to move more quickly, again possibly because they don't have established systems and standards internally whereas larger entities are apt to have you know a greater problem moving and being flexible to the change. I'd also have

to say that I think there's a difference between making modifications to existing systems and existing processes versus doing business process change, or the reengineering of a process and absolutely turning over, let's say for instance a complete document management system. that would go for any size entity. DR. WOODCOCK: DR. BUETOW: technical question. Dr. Buetow? A slightly more And

You spoke relatively

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forcefully against the concept of multiple 3Ps. I'm just curious in today's technical

universe of services-oriented architecture and under the presumption of codified global standards, can you further articulate why the disadvantage of multiple partnerships as opposed to a single centralized entity? MR. ROSEN: Please don't I'm not against

misinterpret what I said. multiple P3s.

I think that there is reason However, if you stop and

for multiple P3s.

look at the examples that I've presented about being able to link across a submission lifecycle, there's obviously a problem if that is located on different physical entities. So I was merely pointing out some

of the drawbacks that may occur if this is not planned and rolled out in an efficient manner. MR. TRIPP: to that. One other thing to add

As you look across a P3 concept and

where some of the savings are, some of the savings and attractiveness if you have a

single disaster recovery plan, you have a single backup and so that maintenance cost gets multiplied depending on how many P3s. DR. BUETOW: That may be in part

answer to sort of a follow-up question. You've mentioned this and I just want clarification of how tightly coupled the service provider should be, or the end service provider should be to the - from your all's perspective to the 3P. Is the 3P -

where do you see the relationship in the service providers? Are they loosely coupled? Does the 3P drive

Are they tightly coupled?

and determine who all the service providers are? MR. ROSEN: I would think that it

is necessitated by the board of directors of say, for instance, CRIX in this instance, and the community of stakeholders at CRIX to ascertain what applications would be running underneath the platform. I would also say

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that the quality of service, the timeliness of service would be mandated by any contract that would be formed between that entity to put applications up underneath that infrastructure. So I would hope for a

tighter relationship rather than a looser one. DR. WOODCOCK: Go ahead. DR. BUETOW: If I could just - and One other question.

we absolutely appreciate this concept of concern of churn of standards. So how do you

all - do you all have a proposed path that we actually standardize the standards? I mean,

this comes back to our incentivized versus -MR. TRIPP: Well, I think we're I

collectively learning together over time. think the HL7 draft standard for test use

model that's been adopted by RCRIM is a good model. We need to have the patients patience

to let it play through and we also need to make sure that get the stakeholders engaged. And in some cases the stakeholders have other

things that are preventing them from getting immediately engaged. I know we talked with

our colleagues in Europe about engaging in some testing on RPS late third quarter, early fourth quarter this year, and we got the answer that they can't participate till first quarter because of other things going on. can't throw up our hands and say, well, we can't wait for you. We have to wait and let We

the process mature if we're going to get a valid standard out. MR. ROSEN: One other comment.

I'd state that the CDISC ODM model and the BRIDG model are helping I think to bring about harmonization of standards across the various communities. MR. TRIPP: Yes, absolutely. Dr. Levin.

DR. WOODCOCK: DR. LEVIN:

Yes, just two things.

You just brought up a point about the testing, but there's a business case for

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having resources for that too and so some people it's going to be the same issues? MR. TRIPP: Yes. I think there

needs to be a well-established test plan for those so that we can go to those people who are stakeholders and say, hey, we need a stakeholder who is willing to test storyboard one, two and three. Because they're related,

it's a short, manageable piece of work. Who's going to step up and do that? And then

four, eight and 15 are related, we need somebody else to pick up that. And I think

we're just collectively learning that those are the kinds of details we need in this. This is a relatively new process as you're aware of. DR. LEVIN: But the same issues as

far as justifying - going back to your management and justifying that resource is going to be the same issues. MR. TRIPP: But I can measure what

that ask is as opposed to I just need an open head count to work on this for ad infinitum.

DR. LEVIN:

My question was back

to the CRIX or public-private partnership. MR. ROSEN: DR. LEVIN: "P3" works, Randy. Okay. Does it have to

- why is it - why did you say not-for-profit? What about a for-profit organization running that? MR. ROSEN: A for-profit

organization running the infrastructure, I think that a number of companies would be reluctant for fear that monopolistic practices could evolve if there was a total lack of competition in a for-profit way. Then certainly the cost of services could be driven up instead of driven down. Additionally I'd mention that the whole idea of the not-for-profit entity itself is indeed to channel any profit that's generated back into the process and thereby reducing the cost not only for all of the founding members, but also for the associate members.

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DR. LEVIN:

Now, the banking

industry with the VISA, that's a for-profit model? MR. ROSEN: DR. LEVIN: No. Their - VISA is a not-

for-profit organization? MR. TRIPP: DR. LEVIN: Yes, it is. How about if you say a

public-private partnership can be other than CRIX? MR. ROSEN: I guess it could be.

It would not be my desire given all the effort of all the many stakeholders who've put numerous hours into that effort over the years. DR. WOODCOCK: All right. We're

going to have to conclude this presentation. Thank you very much for your comments. MR. TRIPP: Thank you. All right. Our

DR. WOODCOCK:

final presenters in this segment of the proceedings are John Rapoza, CEO of JRRapoza Associates, Inc., and Ari Kaliannan, Chief

Executive Member of Newtech Global Solutions, LLC. DR. RAPOZA: Audience, I don't I'm just I'm in

have any specific presentation.

going to make a couple of comments.

the business of basically dealing with generic drug companies and in the process of getting them approved applications. And in

the clients that I deal with there has not been a lot of interest in electronic applications. Primarily the cost, although

there are some. The middle-sized companies have expressed interest and they do have applications they're putting together. The

primary reason I think is the motivation to do this given the fact that the generic drug office is so far behind in these application reviews that they have difficulty seeing the advantages of making a change to a different application format. However, I think the

OGD, the Office of Generic Drugs, is kind of

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making progress in that direction.

I think

with the SPL, implementing and mandating the SPL as part of the application was a very good idea and that's how I got involved with Ari here and he's going to talk a little bit about his document management system. And the other thing I think they're doing which is most helpful is the electronic review which essentially takes the key elements of the application based on the CTD format and allows a very quick review application of the application for what the agency would consider to be adequate information. So I think they're going in the I think it's going to be a

right direction.

long time before you'll see, you know, applications being submitted by small generic companies because many of the drugs that they're chasing just don't have the financial margin to do that. Having said that, Ari is

going to give a little presentation about his system which I became aware with the SPL which is really a lickety-split system for

dealing with transfer of documents.

And he's

going to talk about his systems as well. Thank you. MR. KALIANNAN: I hope I have I take this

learned to use the computers.

opportunity to thank the agency for giving this opportunity for the presentation. My

experience in the license industry is two years. I have been tasked to automate the It has

small generic industry with $16,000. not come yet. rupees. U.S. dollars.

It's not Indian

But I ask the question like what We have only one

software do you have.

commercial graphics systems, nothing else. It's a good place to start with. So we ask

the questions to the users what you are familiar with. Only two that are familiar We started

with this Office, Word and Excel. from there.

What it takes to make use of

these systems more useful to the end users. Since we do not have much expertise or

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collaboration with other agencies, we had to talk to three vendors. We planned on being

Microsoft Office, talking to them, how you can make this Excel as user-friendly for the regulatory environment, how we can make the Office product more useful. They said you

wait for us, Office 2007 will be the answer. We are not going to wait for Office 2007. need something to be done for this year. We So

we started exploring that way with standards and that's why we took the SPL as a reference point to start our work. Having said that, I think that the last two presentations speaks very well about the industry's needs and the standards and of the non-profit organizations. go through this here. I just want to

Basically the business

challenges are editing among the business partners and agencies, especially when your really small companies who do not have dedicated resources and not only one discipline, who has to wear multiple hats. That's a challenge. Dedicating, locating

files across databases and applications. It's good that my company did not have one database system to work with. with file servers. I had to start

Difficulties enforcing

common vent, check-in/check-out processes have to happen because there's none. ought to establish one. We

Lack of integration

and familiar cost-effective document management systems. to ask for it. for $16,000. Any vendor you're going

They are not going to sell it We already cleared one. That

and - that's a challenge. IT. Even though I was given the

title of IT Director, I preferred work in the field first two years first. Without that I

said I will not take over the responsibility. Having spent two years on the field, I take over the responsibility to move forward. Seeing a couple of applications awhile in the market. What we can do with what we have. We used the

That sort of approach we took.

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Microsoft Office Word package to create the SPL example data and we talked to our friends in Microsoft even though they are not the good one for security and standards, but still you have to go with their blessings for some work. So they had a solution called

BTSTAC sort of which basically gives a tool to integrate the XML files. So we tried to

leverage the application, tried to integrate whatever the possible automation we could do within our capacity. Also we talked about

the enterprise systems, links, commercial systems. Even though the mission was there, So we started

there was not enough funding.

out able to - XML for the form and work for the management system using InfoPath tools which is also available with Office, which is very affordable. The question is who is

going to build the path, who is going to validate it, how is it going to happen. So

these are the questions we are to answer for the users first. We took the initial step of doing

one thing first. SPL. CDT.

That's what we did with the

And we are currently working on the We are seeing wherever there is an XML And Also we

there is a place to go and look for. that is how we start the next one.

are working with Microsoft and Alliance program called BioAT trying to put the puzzles together with the various vendors and see how we can play a role in this environment. initiative. Anyway, nothing is more important than compliance security, especially environment like this. Having come to this That should be our next

country without knowing what is 911, I spent the last eight years dispatching, creating software for at least 200 agencies in this country. With no standards you know how

difficult it is to make the systems work together. Finally comes to SPL and escape Spent two years in

the global XML example.

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understanding it.

I saw that if justice can

be done with XML, why we cannot do the pharmaceutical solutions and that's where we are trying to look at it. I just went through the review and put up a couple of action items for our own site, how we are going to deliver this. Again, since this is a regulatory environment, all business processes are to be initiated and entered in the validated state and systems. We already initiated with a We leverage XML

change control process.

data, use the built-in workflow mechanism within the Windows 2003 environment and the upcoming Windows Vista. I don't want to sell

Microsoft products, but somehow the features are available which allow the vendors and give the opportunity to derive some solutions with the tool sets. And that is how we are

going forward developing this ECTD framework. What we do, we do validation by integrating various data sources, including any business applications, including ERP systems, links,

common data systems, document management systems, laboratories. We clear the portal.

We take the repositories in an XML format, integrate them into portal environment so there it's easy for remote access. This is the philosophy behind our two products today, SPL and ECDT, which makes use of the Microsoft Office so it's less training for the end users and it's easy to use. And we take advantage of these We'll do with Windows

facilities portal.

Vista work for management features which allows us to create a cost-effective solution. We are engineers. We applied an

end-to-end system and product management services from design, development, testing and validating. introduction. for questions. DR. WOODCOCK: much. Thank you very This would be my brief With this I leave the podium

Are there questions from the panel?

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Any questions?

All right.

Thank you.

Okay,

what we're going to do is we're going to take realistically a 15-minute break. back here. Please come

We will reconvene and begin Thank you

promptly at 10 minutes after 3:00. very much.

(Whereupon, the foregoing matter went off the record at 2:52 p.m. and went back on the record at 3:10 p.m.) DR. WOODCOCK: reconvene and get started. We are going to Our next speaker

is Mark Rutkiewicz, Director, Quality Assurance, AGA Medical. MR. RUTKIEWICZ: Good afternoon.

I feel a little like a PETA member at an NRA meeting, or actually a cop at a FBI sting. I'm with the medical device industry, one of the companies in the Twin Cities. How many

other people here are associated with the medical device industry? couple of others. Medical. Yay. Oh, I've got a I'm with AGA

We make devices for making

occlusions in the heart for congenital heart

defects, but I'm going to talk today about best practice of sharing electronic documents in the medical device industry. I've been in

the industry about 20 years doing pacemakers, defibrillators, external defibrillators, implantable hearing devices at a few different companies and one of my jobs has been to engineer information so we can make things faster and make change better. I'm going to overview quickly the rules and the history. I really want to talk

about a proposed process we've been using in the medical device industry for managing product information which is just as complex as what we deal with on a submission. actually we are using a model that was actually developed by the high-tech industry. The laptops you see today cost - we can buy them for $500 from Dell. were $5,000. Ten years ago they And

So the high-tech industry has

taken a lot of techniques and configuration

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management, information control and applied it to reduce costs. One thing they've also

done is instead of building it themselves they outsource it so I'm going to talk about a business-to-business model that's been used by the high-tech industry. It also can be

used by the medical device industry and used for submissions to the FDA, but worldwide. Quickly on the device side, I don't know if everyone knows. The types of

submissions that we do are we do PMAs, IDEs, HDEs, 510k's and additional supplements associated with that. For Europe, medical

device companies do either design dossiers or technical files and there's a lot of overlap between those submissions. Canada has licenses. In addition,

Their submission We don't have to

requirements are lower.

submit as many documents for those types of areas. And then Japan and Australia, totally We're not going to get

different animals. into that.

But the rules for creating an

electronic submission for the medical device industry has evolved over time with different authorities and different needs. consolidated with MDD and the AIMD requirements, they standardized this technical file and design dossier which then simplified, at least for medical device manufacturers, not having to submit to every country in Europe. It's always been done as When Europe

books or volumes and PDFs or electronic. We've done some versions of the PDF that the pharma's been doing, and each company also has tracking methods on databases, but they were just typically tracking specific parts of a submission, you know, dates, what kind of submission it was, who it was to, but not the entire submission that's tracked electronically by most companies. A couple

of years ago I ended up doing a pure electronic submission to the FDA. I had a

paper, but it was really done electronically

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with the ENT group for an implantable hearing device. But historically why the submissions are set up the way they are is because every department owns their information. There's a DMR file, there's We've seen a lot of The clinical

clinical files.

technical clinical information.

side isn't as large for a medical device as the pharma side, but there's DHR files, complaint files, engineering report files. They're all managed independently. And what

happens when we create a submission of medical device, you go into each of the areas and you put it together in a binder and you get the submission out. Well, these things

in these other areas can change and they'd be - it becomes very complex when you get into medical device because of the different process interactions and what's interchangeable and not interchangeable, what needs to be submitted and not submitted. So the history has been we create

each submission book and for each country too independently of each other, even though there's a lot of overlap. And then databases

or manual paper methods were used to track these. And one thing that happens with this,

if we submit - a medical device manufacturer submits something to the FDA, you can't cross-link documents that have been approved already. In a medical device company like

ours, we have about five or six different products, either IDE or PMA, but basically the same material, but each time we submit the biocompatibility report and each time the biocompatibility report gets reviewed by somebody over and over again. There's no

reuse which makes the effort by the FDA a lot more difficult. So what I'm going to talk about is some strategies that have been used by the industry, the high-tech industry and the medical device industry. Best practices.

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They've talked about - some of the other speakers have talked about configuration management. There is a process called It's an

Configuration Management 2.

institute that's a national one that actually trains people all over the world. There's

tens of thousands of people that have been trained in this. Aircraft industry is really It also talks

huge in this and military too.

about flexible end configuration management too. You talk about flexible information And they

structures, products and processes.

haven't gotten to submissions, but it's designed to be flexible. I talked about information mapping. I think that's been part of the

process to create the common technical document. You know, defining who your

audience is and organizing the information with XML. I'm going to go over a quick

little information map where manufacturers control their information and talk about open standards. And I think everyone has talked

about this. with this.

XML I think is the way to go I started using XML about eight

years ago for some information management processes and it's still going great today. This is a quick map-out of the CM2 process. Phoenix. They're an institute based out of They're associated with ASU and the

University of Tennessee and they do training on this. And some of the basic concepts here

is that you start with a master document which you're going to submit and then it goes through a change request, a change order and a change implementation process. That can

happen internally or it can happen at a body that's going to be accepting the information. And it's called engineering change request because they're talking product structure, but the same structure can apply to the submission because a submission is made up of chunks of information. A change admin 1 is a

roll-in process that talks about do you want

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to even accept this thing to begin with. so sort of the first step in FDA, is a submission submittable. change order is done. approved? Second step, the

And

Does each section get

And third is a change in admin

where you actually implement and that's a feedback process. This process works

internally at a manufacturer but can also work at a regulatory body. So it's a 3-step process. Part of

the thing with the parts of the submission, each chunk of the submission gets unique identifiers so you can then allow for reusability. Part of CM2 also is status and

revision identifiers for all objects of the submission. This allows you to then reuse You know what rev

linking existing objects.

this part number's at or this document's number at. Understanding interchangeability

so when you make updates to these submissions. We currently have - one of our

PMA supplements out there has 440-some supplements because we also use it for

emergency compassionate use concepts. we're doing these variety of kinds of

So

submissions with our submission, but it's all tied to a base PMA so to be able to re-link that information together becomes complex when you're talking that many supplements. One thing too in the medical device industry versus pharma, and we're talking pharma having you know drugs out there for 40, 50 years. In a medical device

company a lot of - in the pacemaker and implantable defibrillator industry the products were being revised every 18 months and had to get re-approved. So the speed and

the way of making that change, these techniques we started using at some of the bigger companies. Then I started

implementing these concepts to smaller companies and they seem to work really effectively. As going out from CM2 there's a I'm

basic concept on information mapping.

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not going to go into details here, but it's basically organizing and understanding your information types, which is a big key concept in XML, understanding the type of information that is in the document. Regarding here the next slide, what's in a manufacturer? In a medical

device manufacturer there's information inside the company that we have control of and there's information that's outside the company. And part of the submission is

typically combining these things together into one object that combines device master records, what it takes to build a product, design history files, the reports, some regulatory documents that lead in and talk about the submission, clinical documents that are part of the clinical reporting. You

might tie in articles and papers to support the submission. So we want to be able to tie

that all together into a common format. So an example here is a BOM structure. You build material. It's

creating a structure that's different than a standard folder. In a standard I saw

earlier, some of the documents, you create a folder and create folders within folders. In

this one I could link the same object across multiple sections and not have to recreate it. In a submission there's top level object

and then there's lower for each section and you can tie different kinds of documents to the different sections. And then you could

route, as we'll get into a little bit later, you can route each subsection independently for approval either internally at the manufacturer or externally. This basic process is what's been done in the high-tech industry. There's

about 20 key circuit board manufacturers in the world that make most of the circuit boards and most of the electronics that you have around here, your phones and stuff. there are hundreds and hundreds of design But

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people because they end up outsourcing the manufacturing. Those key 20 manufacturers

use one software application for managing the information that they have to create the circuit boards, and all the design houses then follow that standard. And then the

design houses can move from manufacturer to manufacturer and they can get their information consistent to any manufacturing house. So it's a manufacturer-to-

manufacturer-services standard. So the standard we're going to talk about is an XML standard for managing the structure of this information. we talk about XML is paper to web. One thing It's also

machine readable and also it's been done a lot for the documents. That makes a lot of

sense to take the document XML, but combine it with the structure and change management associated with it. So the needs I'm going to be talking about in this process, what the hightech industry has done and what medical

device companies are doing is using a PLM system, a product lifecycle management. talk about lifecycle of a submission. not just a document control tool. We It's

There is -

in a document control tool there's no way of creating a building material. A BOM allows

you to link objects together that have no relationship to each other at all. You'd

have to create separate meta data fields for all the objects to keep creating these different links. The BOM allows you to be The submission then

independently created.

has a - would have a lifecycle by itself too. You know, you could create whatever you needed to. These tools that are out there I can call it whatever I Design

are very flexible.

want, but pending on a review hold.

the information architecture of a submission with all the document types in a submission record. So there's clinical reports and You

records and then there's design reports.

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might have - we submit things on manufacturing process flow information. We'll submit articles and papers. And if you

define a standard architecture for all that information that goes into any kind of submission to the FDA, then we can build submissions that the FDA then can read. With

these, these tools allow you to attach any file type to any of these objects. attach PDF, XML, Microsoft. You can

You can attach

files that nobody can read because a lot of these tools have neutral file viewers that can read 500 file types. We typically put in

in the high-tech industry there's the ability to read a schematic and that's in a unique file type that typically nobody can read. But in a tool like this, a neutral file viewer allows you to read it without having to buy a $500 tool or a $1,000 tool to view it. Design. The design process has Like I said, for

multiple submission types.

medical device industry there's half a dozen

different kinds of submissions but then with biologics and drug there's different other styles. But if they can all be built with And the

the same basic architecture.

electronic submission needs to be designed for approval, electronic approval and routing. So part of this too, like I said, some of the information that goes into a submission, initial regulatory summaries to highlight the overview of what's being contained, supplements, the DMR for the medical device master record, all the specs, drawings, labels, IFUs that are part of the submission, the DHF, all the reports, engineering reports. In the medical device

companies there's a lot of product that's software. There's software in the products

or there's software - the medical device is software. Software instantly doubles or

triples the size of any report because of the

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amount of documentation associated with validating software that's used in a device. Along with the clinical documents, annual reports, postmarket information. So the standard that the high-tech industry is using today is called PDX, Product Data Exchange standard. standardized with the IPC. It's been

It's the

International - IPC is the standards organization for printed circuit boards because they were using it. Multi-part It

standard in how to create structures. focuses on the content between the

manufacturer and the electronics manufacturer service providers. So tying those together

and that's the standard that a lot of work with Intel, Dell, a lot of these companies have used this standard for their information. XML provides a standards way of And there's a

providing simple structure.

standard user group that - I looked this up online. I'm not associated with this group

directly, but Barb Goldstein at NIST is

running this group. Next thing I want to show you is just an example of in my organization what one would look like. We're in the process of

implementing these tools that are used by the high-tech industry. What you see here is This could be It could be

this is a submission record. I gave this a generic number.

the number the FDA assigns when the PMA gets it. That's what I've done in the past is

generically create this and then once we get a number we change the number. and then attach structure to it. Subsection These are

the documents, the reference documents for that subsection. Here's another section with And this just shows the

different documents. BOM explode.

One thing by creating it once,

what happens is we ended up taking it, copy, save as, edit it for Europe. So then we give

a copy of this then to our notified body in Europe and they'd review our submission the

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same way with slight changes.

You get a

different number, but basically the same content. With this kind of structure too you

can click on any of these records and look back and see where it's used. You can see

how many different submissions one document's been used for. What happens then with this is the BOM is created internally and released through a change order process. Then it can I have

be exported out once it's approved. create a PDX file.

And down here is what a -

this is just a file object that's sitting on my desktop when I created this XML. the PDX to the approve body. You send

You can send it

FTP, through the web, send out a CD, whichever method. object called PDX. But basically it's an There's three PDX viewers

out there in the industry, it's like Adobe viewers, that allows you to - this one shows the exact same structure with a neutral file viewer. Same structures, and the files are

all attached so you can click and see them.

So this is neutral. system now.

It's not even in any

It's available for everybody to

use, anybody to use. Then the process would - we didn't end up doing this with the ENT group. We

ended up sending them the CD with the PDX viewer and they were able to use the paper copy for routing, but then for reviewing they were able to take the CD with them and look at it whenever they needed to and just carry it on a CD versus the whole structure. But

the process that normal manufacturers in the high-tech service industry would use is they would take the submission from the design house, route, import it into their system with the structure, break up - that's you know approving this initially is a change implementation as I talked about as far as CM2. Next, break each section up into

different sections for routing for approval. So different groups would get different parts

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of the submission to approve.

Then it would

have to come back together internally and be put on another change order to release the entire submission to an approved status. And

then it allows you to link these record types together across multiple submissions. you received a submission with a report that's been approved previously you'd see that when it gets imported in. And this is So if

what all the contract board manufacturers in the world are doing this structure today. So we were using a PLM tool in the industry, product lifecycle management, not just document control tool. The majority of

medical device manufacturers use PLM tools because we have to have control of our documents. All these tools, there's the

three that the industry uses is Agile, Matrix 1 and PTC from Windchill. PTC. Windchill from

A lot of people do this kind of They're all 21 CFR 11 compliant

structure.

for audit trails and electronic signatures. Agile has a focus, the one we're using. A

lot of medical device manufacturers use the Agile tool. too. There's other ones out there

It becomes a fairly simple tool to A lot of these

track and implement.

manufacturers can implement these things fairly quickly. There's a case study that

Dell ended up implementing their Agile tool in about six months. parts in 30 sites, so. And they were 100,000 A lot of these tools

are becoming easier and easier to use. They've been around for about 10 years. So recommendation here as from the medical device side. Design a flexible and

proven submission process that can take into account all the variations in all kinds of submissions. Use industry standards and best

practices, I'm talking CM2, using some PDX standards or XML standards. shelf tools. custom. Use off-the-

Don't try and create something

A lot of the stuff's out there now

that's available that's a lot easier to use

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than even 10 years ago, so. background.

This is my

So any questions? DR. WOODCOCK: Thank you very And I would

much.

Questions from the panel?

like to mention, Randy Lutter had to leave and Clark Nardinelli who's Director of the Econ staff at FDA is now sitting on the panel. Any questions from anyone? DR. LEVIN: Can you use your

system to submit something in the regulated products submission standard? MR. RUTKIEWICZ: specifics? format? DR. LEVIN: Well, there is a What's the

You mean is there a specific

we're working on a standard in the Health Level 7. It's an XML standard called the

regulated products submission standard. Maybe if you stick around for maybe a couple of speakers will discuss that. MR. RUTKIEWICZ: Sure. Yes, with

these kind of tools, they're designed - as you create different classes of objects you

can create as many different - they're designed to be very flexible. You can create

as many different data fields that can map to existing fields, and then the question is how do you create the standard, the output, the XML and tag it appropriately so it matches the standard. DR. LEVIN: Right, because here

we're working on a - using your recommendations, it's just not the same standard. MR. RUTKIEWICZ: But if it's using

XML, then you can easily translate one XML standard to another because as long as you define the data types and the PDX in this and they map, you can easily create translations that can map to the common. DR. LEVIN: Okay, I think we'd

like to speak to you after the meeting. DR. WOODCOCK: Other questions? I have

All right, thank you very much.

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another announcement. in the ladies room.

There was a ring left If it belongs to anyone

please just come up to me and describe it and you can get it back. Our next speaker is

Jason Rock who is CIO of Global Submit, Inc. MR. ROCK: I can tell you with a

high degree of certainty that ring does not belong to me. I'd like to thank the panel

for allowing us to speak and my name is Jason Rock. As Dr. Woodcock said, I am the CIO of I am also the project lead

Global Submit.

for the HL7 regulated product submission message. And being the project lead for the

HL7 regulated product submission messages allowed me access to a lot of folks in the industry as well within the agency. worked with all the centers so far. I have We have

evaluated a lot of their systems compared to the RPS message. process. We started the testing

We have also done this with several

folks in the industry as well. And today we heard a lot of good presentations on different topics. And what

we're going to try to focus today on in my presentation is cost. And we heard a lot of

things with cost so I'm going to try to not highlight the things that we've already heard, try to go over some of the things that we haven't heard yet. And I'm going to

change my presentation slightly around to focus more on market interactions and market forces, particularly around competition. So

if my presentation seems slightly disjointed, I changed things up slightly because a lot of the content that we've talked about has already been presented. I want to give,

based on the feedback that I've gotten from several review folks that's worked on regulated product submissions, several industry people that I talked to, I want to provide new feedback to you that you haven't heard today. So one of the big issues that we see is on implementing a pure electronic

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standard.

As you heard today, there's a lack That means there's

of resource out there.

not enough people to do the job that we currently have. What I'm going to try to

provide is some solutions to that as well. Then we're going to talk about, again on the same flavor, on how to save costs within the industry. We're going to talk about the

multiple guidances that are out there from the FDA and around the world. We're going to

touch a little bit on the disparate infrastructure, people having the same systems, doing the same jobs. I'm sure the

FDA knows that they have the same systems doing the same jobs. Abbott has the same You know,

systems that does the same jobs.

everyone else has the same systems to do the same jobs. We're going to talk about how we

can consolidate those and we're going to talk about getting input from the industry early on in the process, from the broader industry, not just people that, you know, work at ICH, not just the people that work at the FDA and

how that's really going to help us evaluate our systems earlier in the process. And the

whole focus of today's - of my presentation is really going to be talking about costs. And then I'll probably pepper in a couple of things. I have an idea for a business case

of how we can sell this to management and so there will be some other stuff in there as well. The first roadblock that we need to overcome is the lack of resources that we have in the industry. And you know as most

of you know there's probably not enough hands to do the current job that we have. And the

reason why we don't have enough hands is because we have an industry full of specialists, and that is a lot to do because of the FDA process. People that submit to

devices group that creates PMAs, they're not necessarily trained to do drug submissions so we have specialists. Anytime you have a

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specialist you have a high barrier to entry. The high barrier to entry increases costs. So we need to figure out a way that we can share resources, lower the barrier of entry. That will allow us to have more resources coming in because we'll have a larger market thus decreasing our cost and sharing resources. The next issue that we have, and this is going along the same lines of sharing resources and specialization. is multiple guidances. A lot of that

Multiple guidance for

the same business processes is very costly, costly to the industry. When you have to

submit to CBER a PDF label and to CDER an SPL label, that's not only cost infrastructure and time when people are diverted from different things, it's also very distracting. So wherever possible we need to consolidate the guidances. We also need to start working

on one submission standard throughout the agency, one standard for all the things we're working on, and we also need to reach out to

a global community.

You know, although for

all the same reasons that I've talked about so far about consolidating your resources where most of these companies are global organizations. Although you're going to get

good cost savings and good sharing of resources working internally, we also need to work externally as well. And the first thing that you know give a little story of when we started the regulated product submissions our goal was to create one model that could be used for all regulated products worldwide. And the first

thing that people said was you know it couldn't be done. And a lot of it was You

because of different business drivers.

have in medical devices, they regulate from sunglasses to pacemakers. You have vet

medicines that have hooves, fins, beaks and tails. You have drugs that has 100,000

submissions a year, some of them over a

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million pages.

You have foods that - there's

an active submission out there that's been active for over 30 years and they're still getting information through it. And so

people thought it was very difficult to come together, though it was impossible. So what we did initially was we started off with two groups. It was the On the

medical device group on one hand.

other side we had the drug and biologic group. The drug and biologic group had a They have already worked on Based on

head start.

electronic submissions in the past.

their experience they created up a submission model, a draft submission model that we started to work on. doing the same. The devices group we're

They had the benefit of

working from the drug group because they had a head start. They said that the model They then took

doesn't meet their needs.

that model, made some tweaks to the model. Then we presented it to the drug and biologics group and at that point the drug

and biologics group unanimously voted that this was a better model that served their needs. So what we did at that point is we then started the two groups. We thought this We

was great, we were making good progress.

then asked both groups to come up with a list of priorities that we wanted to do for the project. What we found out is both groups

independently came up with the exact same list. The orders were different, as you can In a device submission you know

imagine.

they have a lot of products, a lot of models you know in a device submission. In a drug

submission there were issues more because they have a standard already. We had issues

more of well we need to be able to communicate back and forth to the sponsor. But we found out the list was exactly the same. One and two was flip-flopped, three, So we

four and five were exactly the same.

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combined both groups and I've been sitting around talking to everybody that's in these groups and everyone's happier that we combined them. We're learning that the drug

folks and biologic folks have a lot to learn from the device folks. The device folks have

a lot to learn from the drug and biologic folks. And I look forward to start bringing

the vet med folks as well as the food people as well. So the one thing we learned from

RPS is that we can work together. Now, here's the action item for the FDA. If we're working together you know

as an industry, we need you to start working together too. We need you to start looking We

at all your processes and procedures.

need you to consolidate your efforts because when we - and for devices, when we have to send the submission and then get an application number, and for drugs the same exact RPS test submission, we have to ask for the application number first, it becomes very difficult. We're going to still have

specialization and specialization increases cost. The next thing, it goes along the same lines, is that the fact that I have the pleasure of working with all the centers in the FDA. You know I'll let you in on a dirty I hope noone from the FDA They have

little secret.

pulls me aside afterwards.

multiple systems that do the exact same thing and that comes from their tracking system. And you would expect that from any large organization. folks. I know I'm talking to industry

They have multiple systems doing the I've talked with members

exact same thing.

of Abbott, letting their dirty little secret out, and they have systems that are only for device folks. They have systems only for the

drug and biologic folks, and they're doing the exact same thing. And the reason why is

because the people they have to deal with on the other end are doing things differently.

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So again, if we consolidate our efforts, work globally, we can get a larger market for the consultants and the vendors. And it's the

competition of that larger market is where we're really going to drive down prices. Because what's very expensive right now is you have a very small market, all these different styles are very small market and you have very few vendors willing to get into those markets. And those very few vendors

when they do get in the market, to recoup their costs they've got to charge a lot of money. Okay, this stops. That's why

everyone that goes into these markets basically almost all the companies focus on the big guys because that's only where they can recoup their costs. They can't justify

charging big pharma millions of dollars and for the exact same system charging a food company five dollars. justify that. They just can't

But if we consolidate and we

can consolidate our markets, you know, we're going to allow more companies to come in

because they're going to see a bigger market. The processes are going to be consolidated so therefore it's easier to get in. And when

it's easier to get in we're going to have more companies. down costs. And this is a couple of things where I'm trying not to throw some criticism any one way, but I want to make comments about other presentations. I think for the More companies always drive

CRIX model it's important to realize that if you have one company that's a not-for-profit or one for-profit company and that's your only vendor that you have to choose for, they're going to cost you more money than 10 companies that are doing the same process. And the reason why is because there's no competition. There's no incentive to be There's no incentive to be

cost-effective. innovative.

So you're going to get worse So although I

products for more money.

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believe in the CRIX model, I think the CRIX model is the way to go, I would urge the board of the CRIX board to allow for-profit vendors, multiple for-profit vendors to plug into the network so that the industry has choice. My last point is from lack of industry, lack of input from the industry. We have good experience both on the regulated side and on the industry side. We need to

leverage those experiences and we need to work with organizations that have the policy and the procedures to allow us to do this in an open environment, in a fair environment. And that's related to standards developed organizations. And we need to focus on

international standards development organizations. We need to focus on

organizations like ISO where we can put our business requirements. We need to focus on

organizations like CDISC where we can work on clinical data. We need to focus on HL7 who

does the messaging, but we need to do it

together.

We all need to do that.

And the

reason why we need to do it together is because the cost is too high if we don't. We've all seen what happened with the ECTD. We've all seen that it came out and there were no vendors that were willing to come out of the gate and say here's a product, start using it. We saw regulatory authorities slow

on the uptake because without the input from industry, without the input from the vendors, without the consultants noone can support us out of the block. So what we need is we need

to all go in the same development organizations where we can all go and then where we can all participate. When we do

that we can evaluate our systems internally, we can see if the standard meets our systems. If they don't we can make recommendations to make them meet our systems. We can probably

do that in a low cost earlier on in the process until we implement and we'll get your

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support, your consultants, your vendors, your software, your software companies out of the block being able to support you. not going to happen immediately. Now it's That's not

going to say, oh, we have a draft standard or a final standard and we're ready to go, but what that means is everyone's been a part of the process and soon after that you know once things are finalized, soon after that people have already been developing. I've talked to

all the vendors that do the ECTDs at least in the United States, most of them in Europe as well, and they're all preparing for regulated product submissions. If this development was

happening behind closed doors they wouldn't know what was going on, they wouldn't know the standard or where it was going and they wouldn't be able to participate early in the process. They wouldn't be able to support

you when the standard is ready. Obviously we need strong leadership. And we're going to need to reach

out to people that we've never traditionally

worked with in the past.

You're going to

have to see all of the agencies, we need the leadership you know from people like Dr. Woodcock and Dr. Levin and Dr. Oliva to tear down the walls of the centers and start working together. We're going to need the

food product associations, pharmaPhRMA, bioBIO and AdvaMed to start working together, start interacting with each other, start making joint recommendations to the FDA. we also need to start working more effectively with our global partners. And And

when our global partners are unwilling and unable to work with us, we need to continue to extend our hand. We need to realize that

to get our true cost savings it's really going to come with working with our global partners. But we also have to realize right

now they might not be able or willing to join us. So we have to constantly communicate We have to tell them we're

with them.

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working in international organizations. We're working in open process. This process

doesn't favor the FDA, or the NIH, or any U.S. companies. into the fold. We also need managerial leadership to realize that it's cheaper to work together than to work in silos. We also need these And we need to bring them

leaderships to come together and fund new positions. To work in standards development

organizations is much cheaper than not to, but it is not cheap. We need reviewers at

the standard development organization table. We need the publishers there. managers there. working together. We need the

We need IT at the table We need people inside

companies whose big part of their job is to work with SDOs and we need people inside the FDA whose a big part of their job is just to work with SDOs and to be a liaison. To sum up, I think I'm okay with time. It's - to sum up real quick, we need

to first and foremost, although I'm a big

believer, we're all - the big cost savings is going to be working with the global community, we need to first look internally. We need to do what we can and the first step is really the FDA needs to take the initiative and consolidate their guidances. We see what's going on in Europe. making a valiant effort. together. They're

They want to work

It's been very difficult and my

opinion is the reason why they're not moving as fast as everyone who I talked to would like to is because they don't have one person, one authority that can say you're mandated, you must start working together. Inside the FDA that's not true. You have the

commissioner that can mandate and says the agencies can work together. So that is

something in my opinion, I know although controversial, in my opinion is where we need to start. We need to work within SDOs in That will show our

international SDOs.

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global partners that we are serious of considering their needs. We also need to get

the feedback from both industry and agency alike. And what this is going to allow us to do, this is going to allow us to share resources. We're going to get improved and This is going to As I said earlier, we

cheaper infrastructure. come from competition.

cannot allow one organization, not-for-profit or otherwise, to monopolize the space. won't be innovative. They

They won't figure out We need to

new ways to make things cheaper. have competition.

And it's very important

that we get industry buy-in early on in the process. And if you're participating at the

table and you're making your feedback into the standards development process and then the standard does not work for you, the only person that you have to blame is yourselves. So in short I believe we do all this, we're going to increase adoption of electronic submissions and hopefully we can do it sooner

than later.

Thank you for your time and I

guess questions. DR. WOODCOCK: Questions from the panel? DR. LEVIN: Thank you. Dr. Levin.

I have a comment.

Just to take time now to talk about the - in standards development organizations it's not easy to develop these standards and get all the people cooperating together. And I just

want to thank Jason for the work he's been doing in the regulated product submissions standard. It's very difficult to get all

those groups together and you've been doing an excellent job in doing that. thank you for that. MR. ROCK: Thank you sir, and I So just to

don't think I could have done that without the support of the FDA, yourself and several industry individuals out there such as Ed Tripp from Abbott, Karen Sailor from Medtronics, and so many of you.

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DR. WOODCOCK: questions?

Any other

Thank you very much. MR. ROCK: Thank you. Our next speaker is

DR. WOODCOCK:

Laurie Rose, Director, Product Management, SAS. MS. ROSE: I am from SAS. Thank you, Janet. And

I am the Director of our

Product Management and Strategy organization for Health and Life Sciences. We looked at

the docket a few weeks ago and decided that based on some of the experience that we've had in the industry for over 30 years and working with the FDA that we might have some hopefully good contributions to make regarding those issues of discussion. And we

do appreciate the opportunity not just to share our thoughts, but also to hear the perspectives of everybody else who has presented today. Two of the areas that we feel probably most qualified to address are - were in the sections around the electronic

submissions about the implementation itself. As not being a sponsor and not having those costs and time issues but supporting those, we wanted to focus more on the implementation. And then also on the section We've provided a

about third party entities.

number of standard tools for the industry for years for analysis and data management, but in more recent years we've also been providing some evolution of our technology to support things like the CDISC standards and the electronic submissions. So we wanted to

focus on that from our experience not just providing those solutions, but also from hosting those for the industry. Before you think too much about that picture, I probably should have backed up, but I think what most people think about a submission they think about an event. There's a timeline. You start a project.

You develop protocols, trial design models.

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You get your statistical analysis plan.

You

start running those trials, collecting data and analyzing those. And at some point you

come to a belief or theory that what you have is in a desired state and it gets packaged up and it becomes a submission. And hopefully

there's been some communication with the FDA along the way with pre-submission meetings, but still viewed more as an event. And for

this discussion today from our perspective we'd really like to take a look at that as more of an ongoing process. Not just an

event, but the electronic submission as a process itself. And part of what we want to

concentrate on is that theory about that electronic platform. What can that be and

what can it hold to better enable this process. We believe that from the sponsor

side you know this is something that would basically have global accessibility. It

would be internet-based so people would basically just need thin clients and access the system anywhere in the world and do that

collaboration in real-time if necessary. That might be somewhere a little bit more in the future. I think one of the questions in

the docket was should there be a phased approach, and certainly developing the tools and the infrastructure to support this does need to be phased. Exactly what would happen

in those different phases needs to be examined I think in more detail to make strong recommendations along that. But

basically with that platform holding things like common tools and even a common shared workspace between sponsors and the FDA to do that review is a recommendation that we would like to make to the FDA and see how that might be able to be accomplished. Also just from the phased approach, if we look long-term, and I've got a slide at the end that will sort of give a little bit more of that futuristic view, but initially I think just being able to handle

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those components and that ECTD lifecycle and the amendments to that, but even further down the road using the same concept and possibly even the same type of platform for postmarketing and reviewing that with sponsors as well. If we look at what might be inside that box, and I'll have a little bit more detail later, but basically there are a lot of technology pieces that have to be put in place and infrastructure from whoever is maintaining those systems to create those firewalls and those partitions to allow for the privacy that's needed so that the sponsors using the system can have their own private workspace for development and testing. And when those elements are at a

point where they want some preliminary review to promote those to more of a shared workspace. We're also looking at the same

type of platform for supporting something like JANUS where the FDA has their own space where they're collecting all of that

information.

You've got probably the best

treasurer of clinical information in the world and being able to mine and analyze and understand that data in a much better way. One of the things that we look at from our own perspective around cost, and we've been providing a hosted system as an offer probably just in the last four or five years now. And we are seeing more and more

of the industry asking us to provide that and give them that service because there are so many benefits. If you look at what a box of

software would cost if you're getting a set of CDs and you're going to take that software and manage it and install it and validate it yourself, there's a certain cost to that and it's certainly going to look lower initially than if you look at the one that's going to be hosted where somebody else is providing hardware and services with that. But we have

seen not just from our own analysis, but more

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from the return on investment analysis of the industry where we're having both large and small pharmas asking to have that hosted because of that reduction in all the resources, not just financial costs, but the burden for IT primarily. I believe it was

ThinSpring earlier who mentioned the exponential cost when you start looking at complexity and just that one validation component. That is something that is an

exceptional part of the puzzle when you look at having to install and maintain and validate a regulatory compliant environment for FDA submissions. I would have to say that we are a very strong supporter of CDISC. We're proud

to have our own staff, Dr. Ed Helton, as one of the board of directors. We also have

member on the Industry Advisory Board and a number of our research development and consulting staff on the technical committees. So we would certainly want to continue that promotion with the FDA to support those

standards.

I think our comment around that

though is that we see both as a vendor as well as working our sponsors trying to implement those standards that they do need to be simplified. There are many and I do, I

believe we lost our CDISC people, but very well aware of the great efforts that have been made to get those standards to a point where they are today where there has been agreement with the industry to come up with a number of those models that they can implement. But we see such a vast array of

difference between the CROs and the sponsors who are implementing those standards. Everything from the ones who are just trying to see how they can cram everything into SDTM at the very end so that they can do a submission using the guidance for SDTM maybe for the first time to those who are really embracing what that business case might be and using those standards throughout the

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entire process, and trying to really gain some of those benefits of using that standard data, especially the global organizations where they've got multiple sites, multiple entities who are contributing a specific study. I think the bottom line in what we're trying to comment here is that there do need to be more tools. And I'll even take a

moment to maybe kick SAS a little bit and the other vendors and the other providers. I

know Octagon provides services to do CDISC transformations. A lot of the sponsors don't They don't know what

know what's available. tools are there.

They're aware of many of

the review tools that have been developed with the FDA through CRADAs, but they don't all apply necessarily to the submission process. And so they just don't really know So for those of us who are

what's available.

providing those tools, we need to probably do a better job of educating the market about those. And then the FDA, we also want to

support having those standard methodologies, whether it's through guidances or the support of those standards for developing an ECTD using CDISC standards throughout the process. Just to liven up and get away from all that text, here's a nice colorful slide with a lot of text on it. Don't want you to

get too bogged down in what's in all of the boxes, but this is basically to sort of take a step into that platform. There would be,

you know, the sponsor's environment, they've got a lot of inputs coming in, they've got clinical data management systems, they've got EDC systems. The one, there's a small box

right in the middle there, that meta data integration, and that's pretty critical because that's where all of that information, whether it's TOX data, PK lab, the clinical information, whatever it is, is going through a process and hopefully as CDISC standards become adopted more, that'll more and more

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become CDISC standard data that's going in through that process and eventually being merged with the documents and the other information into an ECTD. This shows kind of a handoff between the sponsor world and then this shared world where there is this compliant repository, where there are capabilities like audit trails and electronic signatures, a meta data registry that allows that access into the data and the analysis and the results, and then it's all being hosted by a third party system. Now this picture I have This

to say I kind of cheated a little bit. is not a SAS picture, it's really just a

visual, but SAS has experience with something that's very similar to this. I hope most of

you are aware of the FDA pilot that was done with CDISC recently where there was a mock submission. There were a number of industry

players who provided a lot of work and a lot of input, and they actually used SAS's electronic platform to host all of that

information.

So these different parties from

different areas across the country were able to load and put the information in there. And then the one thing that was different is that it was not a shared repository. There

still was that package and handoff at the end. But that mock submission was also done It wasn't done over

in a matter of months. years.

And it was done very quickly, and

hats off to everybody who was involved in that project because it was really amazing how much they accomplished I think between December and September of this year when they presented at the CDISC interchange. But we

certainly would promote that this type of shared environment we do believe would have great benefits in reducing that overall cycle time in running a trial and getting to a submission standpoint. Let me switch gears a little bit to the third party entities. And I'm really

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- we're really approaching this from how we have been used as a service provider in hosting a system for the sponsors and for the industry. The first bullet point there,

neutrality, what I really mean by that is that the person hosting that system does have to be neutral. In other words, there need to

be some definitions around what can be provided by the person doing the hosting. you're hosting, you're providing infrastructure, you're not accessing our touching the data in any way. So that's So

really what we're meaning by "neutrality." The experienced third party is just critical because there are risks, very high risks, that are assumed by that third party when they take on that responsibility. But one of those is to take the risk off of the people using the system. So for example

if you're concerned about audits and whether you're going to pass an audit, you need to have all the standard operating procedures in place. You've got to have the ability to do

that validation and do it correctly to alleviate that risk from the people using the system. On the business process modeling, we believe that that third party can certainly be a facilitator, but should not be dictating what processes are in place especially if we look at a shared environment between the FDA and the sponsors. Those

processes need to be agreed upon by both parties from a business modeling standpoint. And just on the collaboration side, excuse me, I'm hitting a mouse here accidentally. The framework for collaboration - I'll just skip down to that part just a little bit. The security mechanisms have to be put in place. I've heard a lot of people say

security, security, security as well as communication. But that is important, not

just from the physical security of what's in that data center, but also privacy, user

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access, things like that. profiles themselves.

And the user

Whatever is in that

electronic platform, there are going to be a number of different tools and applications. It's not going to be just one system. So

what types of users will be accessing it and what level of access do they need. Do they

need programming access, do they just need to be able to do simple reporting, but understanding those profiles of the people accessing the system. Managing things like

change, the change management procedures and the standard operating procedures in place for that, the whens and the wheres and the hows. And then also having some agreement on

the governance. On the services side, and Jason really - he hit it hard. We really believe

that whatever services are provided, there should be some very standard services for providing the infrastructure, providing the implementation of that and providing some training around the implementation of that

platform.

But additional value-add services,

consulting on how to do things more efficiently using the platform, that's fine for that third party entity as long as it is an openly competitive environment. So Jason I

hit that one hard, and thank you Jason.

agree wholeheartedly with you on that one. The technical services, I believe we also heard some notes about this earlier, but certainly things like disaster recovery and backup and all the planning that are associated with those types of technology services that need to be provided as well. These are some of the attributes that we see that are necessary. The first

one just being 21 CFR Part 11 compliant, and that sort of goes without saying except that there's some complexity in managing a system that has that. So that third party needs to

be able to provide that type of service and that validation. Security, once again,

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whether it's at a user level or a data level within the physical entity itself. the scalability and performance. And then And

certainly as we have gone through some pilots with customers who want to expand users very quickly. We know that you have to be able to The third party

have the ability to grow.

entity needs to be able to expand hardware. They need to have data center capability. They also need to be able to meet the expectations on performance, response time, hitting a button, how long does it take for something to happen. If this electronic

platform is going to enable people to move more towards electronic submissions it can't become a bottleneck so performance is very key. I think we talked about the registry and repositories, basically having a meta data-driven system that allows for data loading and exploration and analysis, reporting. Some of that goes back to those What are their needs going to

user profiles.

be?

What capabilities need to be in there? A couple of additional attributes,

and these have been requests coming specifically from the industry. If there is

an electronic platform, they do want to have that global access, it needs to be web-based. It does need to integrate with different types of tools. It needs to have some And I know

extensibility and openness.

within our company we're looking at things like service-oriented architecture. We have

capabilities within our own system right now. We need to be able to expand those into other areas and other integration with other open tools as well as other industry tools. So

all of those capabilities need to be part of the system as it grows. A lot of people are A lot of the

also requesting more work flow.

smaller organizations, the biotechs, are not - for many of them it's the first time they've done electronic submission and

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anything that you can build into a platform to make that process easier so they have to maybe pay less to those consulting resources that help them is very valuable. We also see

a lot of the larger pharma who would like to have some automation just to speed things up. We also see that it's very important to support that end-to-end process of information flow from HL7 to CDISC and through the ECTD process. And then the

sponsors themselves also want that common area supporting the standard data that they are trying to adopt themselves in their own organizations to do cross-study review. A little bit about that future look. What's in green is a little bit out.

Probably not very many people are using that kind of methodology right now. what's happening in the yellow. It's more It's just a

little bit of a different view of what we've looked at before, but what we believe is that with the electronic platform, as CDISC continues and the organizations really help

start building the standards for the eprotocol and trial model design, that electronic platform is going to be fed with really automatic feeds that are set up with data and meta data coming into the system so that there is a meta analysis. There are

automated procedures for doing that analysis. And the safety and efficacy results of that analysis can then be used to feed back into those systems things like adaptive trials to really help make the whole process more efficient, to take some of that guesswork out each time, to use that information and improve those processes, improve those design models and those protocols as we move forward. Any questions? DR. WOODCOCK: much. Thank you very No? Our

Does the panel have questions? Thank you very much again.

All right.

final scheduled speaker today is Terence

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Zagar who is Chief Technologist at Northrop Grumman Information Technology Health Solutions/Life Science. MR. FISHER: Woodcock. Thank you, Dr.

We have a slight change to our My name is Harry Fisher and I

speaker list.

am the General Manager for Life Sciences at Northrop Grumman. And I'm accompanied by our

Chief Technical Officer Rim Cothran and Terry Zagar, one of our program managers as well. So with that being said generally we'll be talking about the same things. But based on

how the day has gone, and I will say I think I heard someone, I think it was Debra said she had the worst speaking slot. But as I

look at the empty seats I say hmm, I wonder. But I think those empty seats are going to see that the best was left for last hopefully and we can add some value here. So one of the questions we get and one of the areas we're going to address is first off very quickly the question always becomes why is Northrop Grumman here. Don't

you guys build the B-2 bomber? we do do that.

And yes, yes

But we have about an $8

billion IT practice of which about a half a billion of that is for health solutions. what I'd like to offer today is not some theory around some things that might be interesting. I think there's a lot of `Mom And

and apple pie' here that absolutely makes sense from an e-submissions standpoint and we certainly support CRIX. What we'd like to

offer are some specific points regarding the third party entities that we have direct involvement with today and share some experience that could be directly germane to the activities that CRIX could be doing or any potential third party entity. So some of the questions that we wish to address. I'm not going to read

through these, but are around models for setting up a third party entity. I believe

it was Bill Rosen said P3, public-private

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partnership.

What does a P3 look like? What does it

What's the experience with it? cost to ramp up? called monopolies?

What about this thing And is cost-effective

mostly in a competitive environment, a different environment, et cetera, et cetera. So these are the questions that we wish to address. Why is this important for us to talk about this? Well, I've highlighted five

programs that I think can show some various ways to look at the analog of CRIX along with any other type of submission agency that would be involved here. The first one is

AHLTA which is something we do for the Department of Defense and the second one is the Federal Bidirectional Health Information Exchange which we do for the VA. Those two

you can look at together, but what's important about those two? What's important

is that Northrop Grumman runs the largest electronic healthcare record system in the world. It's live. It operates today. So I

know there's been a great deal of talk about EHRs and how they work and how they wouldn't work. We do this today and on a conservative

estimate we have 10 million beneficiaries globally. On an extended beneficiary list we The difference being is

have 20 million.

that on the one hand for the VA we handle things like the technical aspect of how this works. We don't tell them the process. We

don't tell them the content. bidirectional communication.

We allow for And while in

certain cases in certain environments people will say the technology is the last thing you need to worry about. Well, what we find is

if the technology doesn't work nothing else works. For the Department of Defense we do We deal

something a little bit different.

with the processes, the content, the strategies and the technologies underneath of that. So we deal with eight to ten separate

proprietary EHR systems on a global basis and

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try to figure out how to make them all work and talk so that DoD gets what they need for their beneficiary base. The two other ones beneath this, PHIN, NHIN. Rim will talk a little bit more

about NHIN, but we have over a thousand people in Atlanta working on activities like this, a public health information network, and what that means and what the benefit would be to the populace in the U.S., but also because it's a globally-based activity, how do you enforce that. that happen. And then finally what's of interest here and it might be very germane for this discussion as well is MedDRA. We How do you make

are the maintenance and service and support organization for MedDRA. So for anyone out

there who deals with MedDRA, has a subscription to MedDRA, you've dealt with Northrop Grumman. Northrop Grumman maintains And we do

that solely and in completeness.

that under the organization which we'll talk

about a little bit later which is a not-forprofit organization. So when we think about what that means to us and we think about some of these questions, what do we see? Well, when we

think about the question of what are the things that are important, multiple stakeholders. It's almost essential that we

see a public and private entity participation. And we see that very clearly

because in the cases where things actually have to happen, if we don't have both support in the public and private sector then it stops. And for one hand on the public side

what we see is that's where the mandates come, that's where the regs come from. But

if we look in the private sector, if there's not an associated ROI it stops dead in its tracks. If we go down to different

stakeholder needs, it's very, very different. But what you have to always promote is a

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collaborative interoperable environment. Now I'm going to use the case example for what we do, and we do a little bit more of this in MedDRA, but in MedDRA we have stakeholders globally. person management board. We have a 25-

They're made up of

government individuals, NGOs, industry associations, private partnerships, all over the globe. And I can tell you there are some

groups in there who will say no one should ever make money on anything. So how can we Then

actually charge people for MedDRA?

we'll have other people who say well you know what, we should charge them as much as they possibly can bear because then we can invest those funds in other things as well. Now,

we're not in that discussion with the voting member. We're in there to help facilitate

the discussion, but the fact of the matter is we're the ones who implement what comes out of that. So in terms of the different

stakeholder needs we see that. We see workable models for a

public-private partnership in many different ways and some of those we've already discussed. But if you get down to the bottom

line, there are multiple workable models and we're experiencing that right now. going to skip this. this. So I'm

Rim will come back to

But the model that you see here, and

I'm not going to go through all of this, is related back to what we do with MedDRA right now. Now what looks very complex there can And rather

indeed be very, very complex.

than go through that model, you can read through that. How did that evolve? It took

years for that to evolve. of this agreement.

So we're in Year 5

We've just mutually And

extended the agreement through 2011.

what that means is we've gotten really good at doing this. figure it out. investment. And it took a long time to And it cost a great deal of

And so there was a - and I don't

have the graph for this, but you know if you

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look at your investment and finally where you get to the breakeven point, it took a great deal of time to get there. benefit. But here's the

The benefit is that in this area,

that model that you look at, the costs for the average subscriber have decreased by 20 50 percent over the last two years. that? model. Why is

Because we figured out how to do this We figured out how to efficiently get

membership information in to change the schemas as required, to go through the process of medical evaluations and process evaluations, all the different things involved in this. So in any event the way I

look at this is there's something out there that makes sense. And then finally from my side, these are the things that I think will help in terms of separation of responsibilities. One of the things that we don't do both in our public work with MedDRA, what we don't do with our work with DoD and with VA, we don't have a vote. I mean, if the board decides to

go in a certain direction, if the DoD decides to go in a certain direction, we have to carry those orders out. And they have to

make sense, and obviously we have influence over that because we have data and we have observations. But the reality is as you look

at this there's a separation of responsibilities throughout. But the key

that I would leave you with is that it is not a vendor relationship. In this model if we

go forward the stakeholders are vastly different. advantage. advantage. There's certain competitive There's certain non-competitive But if you think that you can

have a vendor perform tasks for the lowest possible price you will get exactly what you pay for. You must invite partnership in this

type of scenario because the folks who will be closest to how things actually work will be the ones who can help you make decisions as to what's the best public interest both

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now and in the longer term.

So with that

I'll turn it over to Rim Cothran to talk a little bit about our experience with NHIN. MR. COTHRAN: Thank you, Harry.

Before we get started on this slide I think the first question you might end up asking yourself is why are we talking about NHIN. mean, NHIN is - the Nationwide Health Information Network is a mechanisms for exchanging clinical information among physicians for point of care. And yes that I

is what the primary goal is, but fundamentally what we're talking about here is an information exchange that takes into account the business processes, regulatory environment, privacy needs and security needs of the health industry. And I think that if

we talk about how NHIN is being developed and the public-private partnerships that are being put in place there to support its development, it gives us at least one model that we ought to look at for other parts of the health industry as well. Also, if we

think about NHIN which is represented as the central circle in this diagram here, it's usually the solutions themselves that people focus upon. Well, what the Office of the National Coordinator for Health Information Technology within HHS put in place was really a number of parallel efforts that all worked in conjunction with each other in order to develop an overall solution. So we'll start

at the top of the chart here and talk a little bit about practices and policies. They established an organization that their charge was to look at the practices and policies associated with privacy of patient information. And it's important whether

you're looking at regulations that are established at state level as it is for clinical care or more broadly at the national level as it is for the regulatory industry, it's important to establish those policies

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and to continue to maintain those policies. Electronic submission, electronic exchange of health information allows for different problems, different issues than we've had in the past and it's important to continue to monitor what policies need to be in place to facilitate it. As we move clockwise around the circle next we reach certification. they also put in place is a separate independent organization charged with certifying systems that end users would end up using. The primary reason for that was to And what

help those end users understand the functionality in a competitive environment. We've already talked a little bit about why it's important that that competitive environment exists, and it is, but it's also important for the end users to understand how different products address the needs in that competitive environment. And certification

and a body that supports certification is important in order to realize that.

So we continue to move around to standards. What they also put in place was a

public-private partnership to identify main standards for information exchange and the implementation guides that should be put in place. One of the things you can say about

the health industry is there are plenty of standards today. And in fact, the HITSP that

is the embodiment of the standards organization identified well over a thousand standards for health information exchange and need to identify exactly which standard were properly maintained, how they were maintained, identify which ones met the needs for information exchange and how they would be interpreted to best implement health information exchange in a uniform environment. As I said, that's a very good

example of a public-private partnership in that that organization is made up of 200 different independent organizations. It

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includes standards development organizations, it includes private industry, that has a stake in this industry and is interested in providing services for it. And government

agencies that are both interested in regulating, promoting as well as participating in that exchange. And then finally we reach back to the Center for Architecture Exploration for NHIN and that is really to bring about solutions for the exchange of health information. What's interesting about the

approach to development of the Nationwide Health Information Network, the NHIN, is not that government was interested in putting that in place or that they were interested necessarily in establishing a single vendor that would own NHIN and that's who you would approach. But instead, inspiring industry to

take on this as an endeavor by funding early organizations to explore different solutions and in a public format describe what those possible solutions were. And in fact, the

culmination of this program is coming up soon in January where the public is invited to see demonstrations of the NHIN that have been developed by a number of vendors working in partnership with all of these organizations. What's important is that these organizations don't only operate as public-private partnerships themselves, but the interoperation between them is also important. The certification body takes

standards that are developed by the standards organization in order to produce the guidelines for certification. And both of

those bodies have to understand the solutions that are being developed as part of the NHIN. If we move on to services, now we talked a little bit already today about the different services that might be developed or might be offered by a third party provider. There are really two different buckets that you might put these services in. The first

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listed here is provider services that are primary services. The electricians and

plumbers that are actually doing the software development, doing the interface development, establishing the infrastructure, et cetera, and we've talked a little bit about that and the need for that to be a competitive environment. Also, the organizations that

maintain the standards as participants in standards development. There's also a need

for secondary providers, certification bodies, auditing bodies, et cetera, that monitor the exchange of information. What's also important though is there is this second bucket. There is an

opportunity for providers of services that actually establish and facilitate the exchange of information. This is a

developing concept within NHIN and ONC today. But the idea that there is a place for an organization that acts in the same way that your internet service provider does, that establishes connections between organizations

and facilitates the movement of information. Some of the services that are necessary to facilitate that for NHIN are listed here and I won't go through all of those because this is specifically about the movement of clinical information, but a few of them are probably interesting to highlight. is the translation. The first

Really what we're

talking about there is an arena where the standards are developing, standards are changing and not yet established and there are legacy electronic systems within the organizations that may want to exchange information. There is a place for an

organization that provides as a service a mechanism to translate between different standards, to transform information from one standard to another to facilitate the easy exchange of information. It takes the burden

off of the exchange in organizations and the receiving organizations, but still promotes

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the use of those standards. Many of the other services that you can imagine here would support routing of information to the right organizations that provides querying of information, et cetera. What you will see missing from this list though is it's not necessarily that this third party organization build a repository to hold all of that, that it is possible to just offer services that facilitate the exchange of information without needing to own that. You can think for instance, again Your ISP does not own

as I turn to your ISP.

your financial information, but facilitates the transmission between your bank and your own financial application at home without actually storing any of that information centrally. And there is a place within the

health industry also for an organization that we've begun to call network service provider that exchanges that information without actually owning it. Terry? So there actually is a

MR. ZAGAR:

Terry Zagar, as everyone knows.

What I'd

like to do is to start to wrap up here and finish up the day. One of the questions I

think that was posed by the FDA was what kinds of things can the FDA do to actually support the establishment of a third party entity and service. I think when we consider

the FDA, there's really two roles that we see. One role is really as a user of a FDA will be a point node if you will

system.

in the contemplated electronic information exchange and so there's specific requirements and those requirements are going to actually represent diverse points of view across the FDA. We also though see that the FDA as a

regulator is very much involved in the review of the system. They will be reviewed in the

validation activities associated with the platform. They will be reviewing the

processes that are being used by all the people who use the system. There's a

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question of that guidance from the FDA also being consistent in terms of how it gets provided. In both of those areas what we

would recommend and what we would like to see is that the FDA speaks with one voice. And

this is important in terms of how this comes across from a standards perspective, but also in terms of what it communicates to the body at large. I think industry does not want to

have to deal with different points of view if you will and the extent to which FDA can help to facilitate that by having coordinated positions and bringing those forward I think would be very powerful. Another area I think where we think FDA can contribute here is really in recognition of some of the stakeholders. We've talked about patients as being one of the stakeholders ultimately when you talk about the efficacy and safety of a product, but one of the - if you look at where a lot of the source data comes from, it's from a medical practitioner who's performing and

supporting clinical trials, collecting information and validating that information is reasonable and rational and that they actually performed or administered in accordance with the protocol. By the same

token though, those same medical practitioners are also involved in other health-related activities over and above just clinical trial support. to day with patients. They're dealing day To the extent to which

you can provide a service that supports both those medical practitioners in the clinical trial realm as well as in their day-to-day activity realm would be very powerful in terms of getting them to buy in. If I looked

at stakeholders today and I said well, who really represented the medical practitioner, I didn't see that voice really here as part of the comment. And we think there's a good

opportunity for some of that discussion as Dr. Cothran talked about what's going on with

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the NHIN.

There's opportunities to leverage

that existing investment that's going on at a national level to say what additional functions can be taken advantage of and leveraged for some of the contemplated electronic exchange here. The final point I think we'd like to address is this whole question, and I think it's come up several times today, of mandates versus incentives. If we go back

and look at MedDRA as a model, if you look at the data in terms of adoption rate from when we started on day one with the MedDRA MSSO in distributing the terminology back in `98 and where we are today, you know it's gone from zero to 1,500 subscribers. But there's been

some very significant spikes if you will in adoption, and those spikes corresponded almost exactly with mandates from the Japanese Ministry of Health, Labor and Welfare that people would use the MedDRA terminology as part of their submissions. Also corresponded to the similar mandate from

the E.U. in terms of the European Medicines Agencies requirements. So I think mandates I

have a role here in pushing adoption. think I have to agree with some of the

comments that were made today though that in mandating the use of electronic submissions, the FDA should do that in the context of a window, a timeframe in which that should occur. It should also exist with a waiver

process for those organizations that for whatever reason are not able to actually accomplish the transition in that timeframe. At least they can establish a plan by which that will happen. We've used that very

effectively in some of the activities we've done that I've been associated with with the SAFE-BioPharma Association in trying to bring in certain providers to support credentialing for a lot of the pharmaceutical companies. On the incentive side we also see that incentives can play a very strong role

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here.

To the extent that there's a business

case I think that helps a lot of the large pharmaceutical and the smaller pharmaceutical companies to participate, but we also see that incentives play a very significant role here in terms of can you reduce - you know, if you submit electronically do you get some benefit in terms of somehow your application or submission goes to the head of the queue. I think those types of activities would be very important to facilitate adoption and to promote it. I don't see that you know

necessarily that the time for review is going to go down with an electronic submission platform. I think more time, you know the

time box is the time box and that will be used for quality purposes rather than for sorting through paper purposes and so you will get better results. And to me that's

the ultimate goal everybody wants. To sort of wrap up, in terms of the question of the concept and the feasibility of a electronic platform

facilitating information exchange, we think that's very feasible and it can be demonstrated. We also think that this whole

question of - I think Bill coined the P3, the public-private partnership term. We very

much think that that's required for success. All the organizations do need to participate and all the stakeholders do need to be represented. And the structure I think, as

Harry talked about such as for MedDRA where there's actually a structure whereby different points of view can be accommodated, but also no single point of view necessarily is pushed over another. And then finally you know is it a single entity that should do this or multiple entities. We're of the opinion that multiple You may start off

entities are required.

small with a single entity because there's no basis if you will from a scalability and from a business case to say we need more

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providers.

But at some point if for instance

this is mandated, then I suspect you would go very quickly to multiple entities to support this. If it's not mandated and has to grow

slowly I think you'll start with a single entity and that will lumber along for some period of time. Again, I think there's

analogs that we've seen out in industry where that's been the case. there's any questions. DR. WOODCOCK: panel? Go ahead. DR. NARDINELLI: backwards. Yes. I'll work Questions from the And with that if

It's not too surprising that when

you get a mandate you would get a spike, but would you say that that's had much effect on your overall trend? I mean are we talking

about just a general upward trend with an occasional spike, or are the spikes, the mandates, driving the upwards trend? MR. FISHER: What we've seen,

generally speaking, is it would look like this. If you looked at the trending it would

go. DR. NARDINELLI: what I'm picturing. MR. FISHER: So it wasn't Right, that's

there's no step function activity. DR. NARDINELLI: It's not a step.

So it's really you know, it could well be described that it's just speeding up what's happening. MR. FISHER: Right. And what you

also see in that regard too is that we do see even today, we see folks drop out. But we do

know generally for a fact, I mean we can't say for certainty, but any organization involved in drug development has a MedDRA subscription now. So I mean that's not And so,

really up for debate at this point.

but the growth period is pretty much over unless we're talking, which we are, about going into the other geographies. DR. NARDINELLI: And then I have

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one other question.

You have actual What is the

experience with falling costs. source?

Is it happening at the platform

itself, or is it at users becoming better at using? MR. FISHER: interesting. Well, it's

From the MedDRA perspective,

which again it's the one that's out there, it's a live one, is that the users themselves don't actually do a lot in terms of the MedDRA process. They take it and they

consume it and what will typically happen is that in a major or smaller or solo practitioner, they simply have - they can interact with the MSSO and then they get the information they need. But what we've

managed to do is we've gotten the process down to where the expectations and what we'll do and how fast we'll do it and then also when we will update the standard, depending on what the basis is, we've managed to get all the stakeholders on the same page so we don't chase that 20 percent with 80 percent

of the cost anymore. it's come out.

That's really where

And so we've learned how to

do this better and so the systems underneath, I mean we've commoditized those. So the

technology underneath, the platform, the hosting, all that, that's being commoditized. DR. NARDINELLI: DR. WOODCOCK: questions? Ken? DR. BUETOW: Could you drill down Okay, thank you. Additional

a little bit deeper for how you all worked in public-private partnership and implemented in the Federal Health Information Exchange with the VA and the Public Health Information Network? Because not to take anything away

from the NHIN, but that feels much more conceptual yet to me, whereas I know you guys actually have boots on the ground and there's actually working systems in PHIN and Federal Health Information. So what is the public-

private relationship, how is it deployed, how

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do you actually deal with the delivery of services? MR. COTHRAN: Well, both of those The It's

two are very different programs.

FHIE/DHIE is a longstanding program. been up for about seven years now in

operation and as you say, where NHIN is still very much conceptual in the pilot stage, FHIE has been operational. That whole program

came about with the VA recognizing that they needed an exchange of information. The real

need was movement of military personnel from the DoD into the VA system and a need for the VA to exchange among its different clinics and hospitals. The VA established the

program itself, identified contractors to develop that system and there is a single system that's put in place at the VA, largely operates itself now. We support that through

technical refreshes, et cetera, but that's primarily a VA-owned system. DR. BUETOW: Go ahead.

So basically in that It is a single

model it is a single system.

contractor who's actually executing and running that particular facility. MR. COTHRAN: That is correct.

Now, as it moved to bidirectional, now we're looking at two agencies interoperate with each other, with the DoD and having a completely separate architecture than the VA system and needing to interoperate among themselves. It turns out that we are now the

single contractor that supports both of those, but that happened through an acquisition. And the truth of the matter is

is it was two separate organizations, two separate contractors that needed to work with themselves and two separate federal agencies that needed to work between each other in order to bring that about. And that was

established before the acquisition, so it wasn't the acquisition that facilitated that. Now if we move to the PHIN, the PHIN is also - it's hard to say when the PHIN

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started.

Often you'll hear people talk about

two or three years ago is when the PHIN was actually established, but the underlying systems that make up the PHIN today, many of them are longstanding. Our support of the

PHIN was again in a very tight partnership with CDC. CDC owns that network. We did not

develop it for them and hand it to them, but it was a give-and-take among both of us. That doesn't mean that while CDC is managing the project that they also architect it, design it, et cetera. We had architects and We would

designers that were part of that. help establish policy.

We'd help establish

standards that were associated with that. And we weren't the only contractor there. Harry mentioned, we are the largest and we support everything that the PHIN does, but there are other contractors that are part of that as well to produce a single product, a single integrated family of applications, but working with a number of different contractors that each interact with each As

other and with the CDC to bring that about. Now if you give me just a second to talk about the NHIN, it is a very different construct than this. And what HHS

is proposing there and what ONC has been promoting is that there is an environment there not for a single solution, but for multiple solutions that need to interoperate with each other. And they started that by

awarding four contracts to four different vendors for only one of them and having them independently establish solutions that would meet the needs of specific organizations that might want to connect. Because all of those

organizations may have different philosophies. And as we move into next

year's activities within NHIN, you're going to continue to see independent solutions there that will probably interoperate with each other. I think the model there that you

should be thinking about is how cell phones

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work, that there are multiple vendors, but whether I am a Cingular or a Verizon customer, I can still call you and it's because those vendors taught the standards necessary that allow them to interoperate with each other. And that's how I believe

NHIN is going to grow up, so it will look different than FHIE will. DR. WOODCOCK: questions? much. Any other

All right, thank you all very

This concludes the scheduled speakers Are there any members

for today's hearing.

of the public who would like to make some comments at this point? If you could take

the microphone there and identify yourself. MR. BARD: name is Bob Bard. Biosciences. Good afternoon. My

I'm with Aastrom

We're a small biotech company I know we try to get

in Ann Arbor, Michigan.

some small industry conversation, but as the panel reviews what they've heard today, and I know it's a lot of information over the last eight hours or so.

We stand at about 16 people. We're in cell tissue and gene therapy. a cell company. We're

The ECTD which was talked

about in great detail is a very rigid kind of document and for us to try to fit in there has been very difficult. In fact, we started

and then pulled back because it just didn't fit. When you listen to some of the people,

especially Edward from PATH, he's a good proponent of this, but he misses part of the things that I have had conversations with him about. We're a small company. He's got

maybe five or six or seven or whatever number of people. In my whole regulatory department I have a clinical When we start looking

there are two of us. department of three.

at these kinds of things, it's very, very difficult. We're very much in favor of In fact, the mandatory

electronic documents.

part of it is one of the ways I am going to push it higher and higher. Think about this

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in great detail though.

There are costs in

personnel training, cost of acquisition of software, cost of acquisition of hardware. There's a multitude of sins involved in this that haven't been brought to light in this meeting and it's not just ECTD. What I came

here for is I though this was a global discussion of electronic submissions. I

remember being at the L.A. District Office I'm going to guess about maybe eight or nine years ago. We were talking about That

registration being all-electronic. hasn't occurred yet.

I'm in great favor of making as much of this electronic as possible, but for small companies, implementation is very, very difficult. What we have to learn as we go, I

have a very big distrust of the vendors that supply this software. I don't know if

they're going to be around tomorrow and I spend anywhere from $20,000 to $100,000, for a small company that's a big expense, and then I have to hope that they're going to be

with us.

As you go through this, I'd like to

see some way of getting this down to a much simpler style. XML is fine. Does it have to

go through a vendor?

Something that could be

more generic, something that would allow us to work. I remember this started off as an

Acrobat system where we had an Acrobat backbone, an Acrobat document. - and it's much more difficult. We've gone to Can we get

to something that works in XML that anybody can pick up and work with it easily because this is getting to a point where you're going to want us to do this and I think as soon as the FDA mandates it, EMEA is going to mandate it, HAN's going to mandate it, everybody that utilizes the ECTD format is going to fall in line and we're going to have electronic submissions as the requirement. I applaud this group coming together, at least giving us an opportunity to listen, but I think there's a lot more to

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be had here.

Taking it all the way and

getting rid of paper is a great idea, I just hope we can do it at small companies because when we start off small we have big hopes. Thank you. DR. WOODCOCK: microphone? questions? much. Can you stay at the

Does anyone on the panel have No? All right, thank you very If you

Other members of the public?

can come up to the microphone and identify yourself. MR. BRENNAN: Centocor, J&J. Michael Brennan from

There's been a theme that's

come through a couple of the presentations that first started with Al's talk early this morning about do we have the right people, do we have the right skills. I think most of

the responses, most of the discussion really focused on the technical aspects of, you know the staring at a computer and hitting the right keys. But I think what we have to

recognize is the marriage between people that have the content knowledge, the regulatory

knowledge merging with the information processing, it's a very transformational change that needs to happen within our processes. Randy, you challenged in terms of what's the impact on our business processes and if you're going to move to fully electronic, we need to have that marriage within our companies. We need to have people

to focus on the role of being an information manager. Not an IT manager, but a true

information manager. DR. WOODCOCK: The younger Couldn't

generation provides us some hope. resist one editorial comment. from the panel? Thank you.

Any questions Are there any Yes.

further comments from the audience? MR. KUBECK:

Hi, I'm Bill Kubeck. We are a We just

I'm from Steeple Laboratories.

small pharma company, second tier.

migrated from third tier to second tier.

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Very proud of that.

We are 150 years old and

we're really good at paper. And a number of comments that were made in terms of the business case on going from paper to electronic. question all the time. Paper, I get the

We've got the papers. Migrating to

We can just continue to do it.

electronic submissions is - there is a significant investment in terms of the IT infrastructure. The total cost of ownership

can be quite great, three to ten times the original amount in terms of acquiring the actual technology to do so, in terms of just corporate personnel, in terms of training. Steeple Laboratories are great supporters of standards. We're involved in

the creation of standards and we want to go fully electronic. But we need to also

understand, we file, we have branded pharmaceuticals, we have generics, we have OTCs, we have cosmetics, and by the way, we register our products in a hundred different countries with all these different standards.

The issue for us is how can we effectively manage our submission information to all these different regulatory agencies and all these different standards. Now if we just

even look within the United States there are a multitude of standards depending upon which division we're talking to. Question to the

panel is when can we expect to have an integrated standard for submissions? DR. WOODCOCK: Well, under a Part

15 hearing you're not permitted to ask the panel questions. that question. However, I will respond to The FDA has formed a cross-

agency bioinformatics board and we are engaged in this very moment in developing the plans for converging our standards across all the different FDA areas. And that does not

mean, as we've just heard from you, that the hundred regulatory agencies around the world are going to fall in line with us, but if we have a strong and we work in a public-private

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partnership I think towards consensus standards we can go far that way. point is well taken. But your

We recognize that.

We've heard that actually from many other speakers today. MR. KUBECK: terms of migration. compliant. One last point in

We are not ECTD-

We're making the full transition.

Now comes the issue in terms of getting the public awareness of RPS. And I would like I

your thoughts in terms of that transition. can't go, you know again, for my senior management to embrace going to electronic submissions the question they're asking us, ECTD right? And that's the question mark. DR. WOODCOCK:

I think as people -

please submit to the docket issues you have around those particular timing and communication issues that would be very helpful. Did anyone on the panel have Thank you very

further questions on these? much.

Yes, from another volunteer. MS. AZEVEDO: Good afternoon Dr.

Woodcock and the panel. DR. WOODCOCK: yourself? MS. AZEVEDO: Antoinette Azevedo. My name is Can you identify

I'm President of e-

Submissions Solutions, a professional services firm assisting companies in selecting and implementing and validating document management and publishing. I also

provide submission publishing services. Point one. I tried to comment to

the notice that was sent out and the web link didn't work. DR. WOODCOCK: addressed. That's I think been

We're sorry about that. MS. AZEVEDO: Okay. Secondly, I

work with companies that are sometimes prior to the IND phase. And I've worked with them I've been in One of the factors

for the last six years. business about six years.

that prevents companies from starting INDs in

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the ECTD phase is the fear that if they start ECTD, always ECTD and that will prevent them from licensing out products because the business model is to be virtual license out or sell out and they're afraid that that will be an impediment to doing a deal with a partner. So that's one interesting factor.

So if ECTD were mandatory throughout the lifecycle, this would remove an impediment to starting in the IND phase. The other issue is a training factor. I, because I provide submission

publishing services, I have a boutique operation and oftentimes go into the customer environment and work on the systems that the customer has already purchased and validated. And the customers can't find people to operate their own systems so they bring in consultants. Secondly, in my practice I have a need for consultants to come and help me execute my projects and it's impossible to find people of the right skills to perform

the functions.

And the skills are not just

the regulatory skills which was - is really critical, it's the computer skills. It's

also the knowledge of the applications, how to use Microsoft Word to go to PDF, how to troubleshoot problem PDFs. Recently we used

Global Submit to validate a submission I was working on, and this is a vendor's system that has been used to produce many ECTDs submitted to the FDA including pilots. And

we found lots of issues reported by Global Submit that were surprises, including issues with the standards themselves. That is,

there are issues with the ECTD, DTD and with various lists and so on that caused false positive issues to be reported by the validations. This whole set of things are

big impediments, but if there were mandatory requirements with an appropriate timeframe and outreach by the agency to especially the small, the tier three and tier two companies,

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really critical to making this a success. DR. WOODCOCK: questions? No. Thank you. Any I

Any further comments?

think we may have time for one last comment here. Yes. MS. PALLA: I'm Madeline Palla. And I

I'm with the Animal Health Institute.

just wanted to comment that the animal health industry is often slightly CDER and CBER in electronic requirements and we monitor these issues closely and it's going to be very complicated in the animal industry to know and conceptually to give you an idea. Listening to the speaker today talk about you know having a notepad laptop to, you know. veterinarian out of the office is not going to be able to utilize that. And I just wanted to, I cannot speak necessarily to the costs personally as I am with a trade association and not a particular sponsor company, but a lot of our animal health companies are divisions of larger human pharmaceutical companies and so A

it may not be as great of an impact to those companies that are already implementing these requirements in other areas of the corporation. But for some of our animal

health companies that are solely animal health it's going to have a large impact. And we do plan to answer the other questions in the notice in our comments that we submit. Thank you. DR. WOODCOCK: right. Thank you. All

Is there one more person who wants to All right. We have a few more

contribute? minutes here.

MS. VATLEIT: Stephanie Vatleit.

Thank you.

Hi, I'm

I'm with Animal Drug

Alliance and I would mirror in large part the AHI position. We are cautiously optimistic

about electronic submissions, but we sense some real hesitancy on the part of CBN to work with us on those submissions and a hesitancy on the part of our member companies

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to work through the business case.

We've

heard a lot about that today and it is really important to the bottom line as there are lower margins on the animal health side as you might expect. And we would also like to acknowledge that it's not only a burden to get the software and hardware necessary for making electronic submissions on the part of the sponsors, but also on the part of the centers. And I think that's a real concern. DR. WOODCOCK: Questions? No. Thank you. I would like to

All right.

reiterate first that the comment period remains open. We hope those of you who have

benefitted today from all the comments, it should inform your comments to the docket. We hope for a robust set of comments that will allow us, NIH and the FDA to move forward in our various venues. thank the panel very much. I want to

I'd like to thank

Paula McKeever for putting this meeting together. She did a fantastic job. I think

we learned a tremendous amount.

And I'd like

to thank all of you who stayed till the end for your attention. Thank you very much and

this hearing is closed. (Whereupon, the foregoing matter went off the record at 4:56 p.m.)

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